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

INTRODUCTION

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

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

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

METHODS

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

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

Statistical analysis

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

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

RESULTS

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

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

 

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

 

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

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

 

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

 

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

Patients	Without events (N = 151)	Some MACE (N = 62)	P
Clinical characteristics
Age, years	62.99 ± 12.37	65.29 ± 13.93	.234
Sex, make	115 (76.2)	47 (75.8)	.956
Arterial hypertension	107 (70.9)	456 (74.2)	.623
Dyslipidemia	93 (61.6)	41 (66.1)	.533
Diabetes	39 (25.8)	22 (35.5)	.157
Smoking habit			.808
Active smoker	64 (42.4)	28 (30.4)
Former smoker	19 (12.6)	9 (14.5)
Family history of coronary arteriopathy	17 (11.3)	4 (6.5)	.285
Kidney disease (CrCl < 30)	8 (5.3)	7 (11.3)	.120
Peripheral vasculopathy	9 (6.0)	10 (16.1)	.018
Aortopathy – aneurysms	3 (2.0)	4 (6.5)	.097
Atrial fibrillation	5 (3.3)	3 (4.8)	.594
Connective tissue disease	0	3 (4.8)	.006
LVEF	56.62 ± 9.74	53.67 ± 13.44	.080
Previous revascularization	36 (23.8)	13 (21.0)	.651
Angiographic characteristics
Right dominance	127 (84.1)	53 (85.5)	.237
Serious coronary stenoses	147 (97.4)	60 (96.8)	.817
1 vessel disease	47 (31.1)	19 (30.6)
2-vessel disease	52 (34.4)	22 (35.5)
3-vessel disease	48 (31.8)	19 (30.6)
Location of the aneurysmb			.429
Left main coronary artery	3 (2.0)	0
LAD	88 (58.3)	44 (71)
LCX	41 (27.2)	12 (19.4)
RCA	41 (27.2)	18 (29.0)
Type of aneurysmc			.676
Fusiform	62 (41.1)	28 (45.2)
Saccular	86 (57.0)	33 (53.2)
Giant aneurysm	4 (2.6)	4 (6.5)	.185
Number of aneurysms per patient
1	122 (80.8)	48 (77.4)
2	20 (13.2)	12 (19.4)
3	6 (4.0)	0
4 or more	3 (2.0)	2 (3.2)
Indication for catheterization, acute	101 (66.9)	54 (87.1)	.002
Indication for catheterization			.053
STEACS	38 (25.1)	17 (27.4)
NSTEACS	61 (40.4)	34 (54.8)
Heart failure	2 (1.3)	1 (1.6)
Stable angina	33 (21.8)	5 (8.1)
Other	17 (11.2)	5 (8.1)
Type of stent			.598
Stent-graft	13 (8.6)	4 (6.5)
Drug-eluting stent	138 (91.4)	58 (93.5)
Size of the stent-graft, medians
Diameter	3.38 (3.0-4.0)	3.28 (3.0-3.5)	.521
Length	22.00 (15.0-28.0)	21.74 (15.0-25.0)	.843
Intracoronary imaging modalities
IVUS	17 (11.3)	7 (11.3)	.995
OCT	8 (5.3)	0	.065
Median follow-up, months	34.0 (12.0-76.0)	46.93 (18.75-79.75)	.646
CD: coronaria derecha; CX: circunfleja; Cr: creatinina; DA: descendente anterior; FEVI: fracción de eyección del ventrículo izquierdo; IVUS: ecocardiografía intravascular; MACE: eventos adversos cardiovasculares mayores; OCT: tomografía de coherencia óptica; SCACEST: síndrome coronario agudo con elevación del segmento ST; SCASEST: síndrome coronario agudo sin elevación del segmento ST. Los datos se expresan como n (%) o media ± desviación estándar. a Se consideró como MACE el combinado de muerte de cualquier causa, ingreso por insuficiencia cardiaca, angina inestable, reinfarto, ictus, embolia sistémica, sangrado que precisó atención médica o cualquier complicación del aneurisma (crecimiento, nuevo aneurisma, reestenosis o trombosis). b Hay más aneurismas que pacientes, porque cada enfermo puede presentar varios. c En varios pacientes (3 y 1, respectivamente) el aneurisma fue considerado mixto.

 

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

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

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

 

DISCUSSION

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

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

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

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

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

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

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

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

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

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

Limitations

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

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

CONCLUSIONS

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

FUNDING

None.

AUTHORS’ CONTRIBUTIONS

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

CONFLICTS OF INTEREST

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

REFERENCES

INTRODUCTION

Physiological evaluation has a class IA recommendation to guide coronary revascularization in the current clinical practice guidelines.1 Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) have proven to be safe tools to guide revascularization therapy in several clinical scenarios.2-4

The results of the DEFER trial at the 15-year follow-up showed the long-term safety of FFR to defer therapy in functionally non-significant stenosis.5 Afterwards, the DEFINE-FLAIR and the iFR-SWEDEHEART trials proved the non-inferiority of the iFR compared to the FFR to guide revascularization of moderate stenosis at the 1-year follow-up.3,6 The utility of physiological guidance to guide revascularization in multivessel disease has been confirmed in the FAME and the SYNTAX II clinical trials.7,8

However, the prognostic value of pressure guidewire assessment in certain high-risk groups has not been firmly established yet. A pooled analysis of the DEFINE-FLAIR and the iFR-SWEDEHEART trials found a higher rate of events in patients with acute coronary syndrome in whom revascularization of non-culprit vessels was deferred based on the FFR or the iFR compared to stable patients.3,6 Patients with diabetes mellitus (DM) are a high-risk group with a well-known higher burden of cardiovascular disease and worse prognosis including more extensive atherosclerosis, more prevalence of multivessel disease, and a faster disease progression compared to non-diabetic patients.9-11 The special characteristics of the extent and spread of atherosclerosis in patients with DM raises concerns on the safety surrounding deferring revascularization in this population. Our objective was to evaluate the safety of revascularization deferral based on pressure guidewire interrogation in diabetic patients at the long-term follow-up.

METHODS

Study population

This is a single center, retrospective, and open-label trial. The study population was recruited from a total of 1321 consecutive patients with coronary artery disease in whom the iFR or the FFR indices were used to determine the need for coronary revascularization from January 2012 through December 2016. In 444 patients (34%) the revascularization of ≥ 1 lesions was deferred based on FFR values > 0.80 or iFR values > 0.89. Patients with stable angina and acute coronary syndrome (with non-culprit stenosis interrogated with pressure guidewires) were included in the study. For the analysis, the overall population was divided into 2 groups: DM and non-DM. The DM group was defined based on their past personal history included in their medical records. The study flow chart depicting patient selection is shown on figure 1.

Figure 1. Study flow chart. iFR, instantaneous wave-free ratio; FFR, fractional flow reserve.

This retrospective, cohort study was conducted according to the principles established by the Declaration of Helsinki. Both the informed consent and the research committee assessment were spared due to the retrospective nature of the study; each patient included in the database was encrypted and de-identified to protect everyone’s privacy.

The physiological procedure

Pressure guidewire assessment was performed using a commercial guidewire (Verrata, Philips Healthcare, United States; PressureWire [Certus. Aeris, X] St. Jude Medical, United States) and the standard technique previously reported.3,12 As a standard practice, an intracoronary bolus of nitrates (200 mcg) was administered before the FFR or iFR measurements. The cases submitted for FFR assessment received IV adenosine at a rate of 140 µg/kg/min. The cut-off values to defer revascularization were FFR > 0.80 or iFR > 0.89. The presence of significant drift was discarded by placing the sensor of the pressure guidewire on the tip of the guiding catheter at the end of the physiological measurements acquisition.

In patients with stable angina, the physiological evaluation was performed as part of the same procedure, and all intermediate stenoses were assessed. In patients with acute coronary syndrome, interrogation with the pressure guidewire was performed at a staged procedure in non-culprit vessels only.

Endpoints

The primary endpoint was the 4-year risk of major adverse cardiovascular events (MACE) defined as a composite endpoint of all-cause mortality, myocardial infarction or unplanned target vessel revascularization (TVR). The secondary endpoints were a) the individual components of MACE, b) the rate of target vessel myocardial infarction, and c) the rate of unplanned TVR based on the physiological index used (FFR or iFR)

Statistical analysis

Continuous variables were expressed as mean ± standard deviation (SD). Discrete variables are summarized as frequency (percentages). Under baseline conditions, group comparisons were made using the Student t test or the Mann Whittney U test for continuous variables and Pearson’s chi-square test for discrete data.

Time-to-event analysis was performed using the Kaplan-Meier method, and group comparison was performed using the Mantel-Cox (log-rank) test. For the primary and secondary endpoint comparison between diabetics and non-diabetics, a Cox Proportional hazards model was used to estimate hazard ratios (HR). The adjusted analysis was performed based on age, sex, hypertension, dyslipidemia, smoking habit, chronic kidney disease, previous stroke, previous percutaneous coronary intervention, and coronary artery bypass graft surgery.

All probability values were 2-sided with 95% confidence intervals (95%CI). P values < .05 were considered statistically significant. The SPSS version 23.0 (IBM Corp, Armonk, NY, United States) and STATA version 15 (Stata Corp, College Station, TX, United States) statistical packages were used for statistical analyses.

RESULTS

Baseline clinical and angiographic characteristics

The baseline clinical characteristics are shown on table 1. In the overall study population, mean age was 68.4 years, and 39.6% were patients with DM (164 patients). As expected, patients with DM had more cardiovascular risk factors and comorbidities compared to patients without DM. There were no significant differences in the clinical presentation between both study groups (P > .05). Most patients received optimal medical treatment at the hospital discharge without significant differences between DM and non-DM patients (P > .05).

 

Table 1. Baseline characteristics

	Total (N = 444)	Diabetics (N = 164)	Non-diabetics (N = 280)	P
Clinical characteristics, N (%)
Sex				.026
Male	340 (76.5)	116 (70.7)	224 (80.0)
Female	104 (23.4)	48 (29.3)	56 (20.0)
Age (year)	68.41	70.02	67.46	.003
Arterial hypertension	321 (72.3)	138 (84.1)	183 (65.4)	<.001
Hyperlipidemia	287 (64.6)	124 (75.6)	163 (58.2)	<.001
Current smoker	253 (57.0)	85 (51.8)	168 (60.0)	.093
Chronic kidney disease	41 (9.2)	29 (17.7)	12 (4.3)	.000
COPD	30 (6.8)	9 (5.5)	21 (7.5)	.415
Previous cerebrovascular disease	21 (4.7)	12 (7.3)	9 (3.2)	.049
Peripheral vascular disease	38 (8.6)	18 (11.0)	20 (7.1)	.164
Previous AMI	47 (10.6)	17 (10.4)	30 (10.7)	.908
Previous PCI	220 (49.5)	70 (42.7)	150 (53.6)	.027
Previous CABG	13 (2.9)	9 (5.5)	4 (1.4)	.019
Clinical presentation, N (%)
Myocardial infarction	148 (33.3)	46 (28.0)	102 (36.4)	.302
Unstable angina	89 (20.0)	33 (20.1)	56 (20.0)
Stable angina	112 (25.2)	44 (26.8)	68 (24.3)
Silent ischemia	46 (10.4)	22 (13.4)	24 (8.6)
Other	49 (11.0)	19 (11.6)	30 (10.7)
Therapy at discharge, N (%)
Aspirina	408 (93.8)	150 (94.3)	258 (93.5)	.720
Clopidogrela	165 (37.9)	53 (33.3)	112 (40.6)	.134
Prasugrela	22 (5.1)	9 (5.7)	13 (4.7)	.663
Ticagrelora	78 (17.9)	30 (18.9)	48 (17.4)	.699
DAPT	332 (56.3)	111 (52.6)	221 (58.3)	.181
Statinsb	396 (93.2)	148 (93.1)	248 (93.2)	.952
Beta-blockersb	334 (78.6)	121 (76.1)	213 (80.1)	.334
ACEIb	324 (76.2)	126 (79.2)	198 (74.4)	.260
Acenocoumarola	41 (9.4)	18 (11.3)	23 (8.3)	.304
Insulin	53 (8.9)	53 (24.8)
ACEI, angiotensin converting enzyme inhibitors; AMI, acute myocardial infarction; CABG, coronary artery bypass grafting;; COPD, chronic obstructive pulmonary disease; PCI, percutaneous coronary intervention. a n = 435. b n = 425.

 

Characteristics of vessels with deferred revascularization

On average, deferred revascularization was performed in vessels with stenoses of intermediate severity (percent diameter stenosis, 59.73% ± 9.2%). The most frequently interrogated artery was the left anterior descending coronary artery (43.2%). In most patients, only 1 vessel was deferred (72.7%). Nevertheless, in about 4% of patients, revascularization was deferred in 3 vessels within the same procedure.

In our study population, revascularization deferral was based more frequently in the FFR (434 vessels, 73.2%) compared to the iFR (159 vessels, 26.8%). The same ratio applied to patients with DM: revascularization was deferred in 157 vessels (73.4%) based on FFR values compared to 57 vessels (26.6%) based on iFR values. The mean FFR and iFR values of the overall population were 0.87 ± 0.46 and 0.94 ± 0.41, respectively without any significant differences between diabetic and non-diabetic patients (table 2).

 

Table 2. Characteristics of the deferred arteries

	Total (N = 593)	Diabetics (N = 214)	Non-diabetics (N = 379)	P
Deferred vessel
LMCA	25 (4.2)	8 (3.7)	17 (4.5)	.664
LAD	256 (43.2)	90 (42.1)	166 (43.8)	.681
LCX	173 (29.2)	59 (27.6)	114 (30.1)	.519
RCA	138 (23.3)	57 (26.6)	81 (21.4)	.145
Number of deferred vessels per patient*
1 vessel	323 (72.7)	122 (74.4)	201 (71.8)	.475
2 vessels	98 (22.1)	35 (21.3)	63 (22.5)
3 vessels	19 (4.3)	7 (4.3)	12 (4.3)
4 vessels	4 (0.9)	4 (1.4)	0 (0.0)
Coronary physiological parameters
Mean FFR	0.87 ± 0.46	0.86 ± 0.41	0.87 ± 0.48	.387
Mean iFR	0.94 ± 0.41	0.94 ± 0.43	0.95 ± 0.40	.091
Deferred based on FFR values	434 (73.2)	157 (73.4)	277 (73.1)	.942
Deferred based on iFR values	159 (26.8)	57 (26.6)	102 (26.9)	.942
FFR, fractional flow reserve; iFR, instantaneous wave-free ratio; LAD, left anterior descending coronary artery; LCX, left circumflex artery; LMCA, left main coronary artery; RCA, right coronary artery. * n = 444.

 

Clinical outcomes at the long-term follow-up based on the presence of diabetes

The median follow-up was 43 months [interquartile range, 31.1-55.8] without any differences being reported between DM and non-DM patients. The clinical outcomes are shown on table 3. Diabetic patients had higher rates of MACE (33 [20.1%] vs 37 [13.2%] in non-DM patients) although this difference did not reach statistical significance in the adjusted analysis (HR, 0.98, 95%CI; 0.46-2.11, P = .964). The all-cause mortality rate was higher in diabetics (18 [10.8%] vs 15 [5.3%] in non-diabetics), but the rates of cardiovascular death were not statistically different in either group (3.1% vs 2.1%). A trend towards a higher rate of myocardial infarction was seen in patients with DM (6.7% vs 2.9%; P = .063), yet target vessel myocardial infarction was similar in both groups (HR, 0,87; 95%CI, 0.15-4.89, P = .906). Similar rates of unplanned revascularization and TVR were seen between diabetics and non-diabetics (figure 2 and table 3).

 

Table 3. Clinical events at the 4-year follow-up based on the presence of diabetes

	Diabetics (N = 164)	Non-diabetics (N = 280)	Unadjusted analysis		Fully adjusted analysis*
			HR (95%CI)	P	HR (95%CI)	P
MACE	33 (20.1)	37 (13.2)	1.58 (0.99-2.53)	.058	0.98 (0.46-2.11)	.964
All-cause mortality	18 (10.8)	15 (5.3)	2.10 (1.06-4.17)	.034	2.01 (0.92-4.40)	.079
Cardiovascular death	5 (3.1)	6 (2.1)	1.45 (0.44-4.74)	.543	0.72 (0.19- 2.76)	.641
Myocardial infarction	11 (6.7)	8 (2.9)	2.54 (1.02-6.32)	.045	2.56 (0.95- 6.91)	.063
Unplanned revascularization	17 (10.4)	20 (7.1)	1.53 (0.80-2.93)	.195	1.55 (0.77- 3.10	.219
	Diabetic vessels (N = 214)	Non-diabetic vessels (N = 379)	Unadjusted analysis		Fully adjusted analysis*
			HR (95%CI)	P	HR (95%CI)	P
Target vessel myocardial infarction	2 (0.9)	4 (1.1)	0.96 (0.18-5.23)	.971	0.87 (0.15-4.89)	.874
Target vessel revascularization	10 (4.7)	16 (4.2)	1.15 (0.52-2.54)	.767	1.14 (0.38-3.42)	.814
95%CI, 95% confidence interval; HR, hazard ratio; MACE, mayor adverse cardiovascular events (all-cause mortality, myocardial infarction, target vessel revascularization). * HR and P values are obtained after adjusting the model with different baseline variables (age, hypertension, dyslipidemia, smoking habit, chronic kidney disease, previous percutaneous coronary intervention, and previous coronary artery bypass grafting).

Figure 2. Clinical outcomes in diabetic and non-diabetic patients at the 4-year follow-up. 95%CI, 95% confidence interval; HR, hazard ratio.

Clinical outcomes at the long-term follow-up based on the physiological index used to defer revascularization

In patients with DM the physiological index used (FFR or iFR) that led to revascularization deferral was not associated with a significant difference in the rate of MACE (P = .688) or with significant differences in all-cause mortality, cardiovascular death, myocardial infarction or unplanned revascularization. Similar rates of target vessel myocardial infarction were seen in patients deferred with both techniques (DM or non-DM) (table 4).

Table 4. Clinical outcomes at the 4-year follow-up based on the technique to defer revascularization

	Patients deferred based on FFR values (N = 347)	Patients deferred based on iFR values (N = 97)	P (log-rank)
MACE	59 (17.0)	11 (11.3)	.288
Diabetics	27 (21.1)	6 (16.7)	.688
Non-diabetics	32 (14.6)	5 (8.2)	.277
All-cause mortality	25 (7.2)	8 (8.3)	.574
Diabetics	13 (10.2)	5 (13.9)	.417
Non-diabetics	12 (5.5)	3 (4.9)	.972
Cardiovascular mortality	8 (2.3)	3 (3.1)	.593
Diabetics	4 (3.1)	1 (2.8)	.964
Non-diabetics	4 (1.8)	2 (3.3)	.436
Myocardial infarction	16 (4.6)	3 (3.1)	.762
Diabetics	10 (7.8)	1 (2.8)	.396
Non-diabetics	6 (2.7)	2 (3.3)	.596
Unplanned revascularization	33 (9.5)	4 (4.1)	.133
Diabetics	16 (12.5)	1 (2.8)	.112
Non-diabetics	17 (7.8)	3 (4.9)	.542
	Patients deferred based on FFR values (N = 434)	Patients deferred based on iFR values (N = 159)	P (log-rank)
Target vessel myocardial infarction	4 (0.9)	2 (1.3)	.527
Diabetics	2 (1.3)	0 (0.0)	.433
Non-diabetics	2 (0.7)	2 (2.0)	.172
Target vessel revascularization	24 (5.5)	2 (1.3)	.037
Diabetics	10 (6.4)	0 (0.0)	.064
Non-diabetics	14 (5.1)	2 (2.0)	.244
iFR, instantaneous wave-free ratio; FFR, fractional flow reserve; MACE, mayor adverse cardiovascular events (all cause-mortality, myocardial infarction, target vessel revascularization).

The rate of TVR was significantly higher in patients deferred based on FFR values compared to patients deferred based on iFR values (24 [5.5%] vs 2 [1.3%], P = .037). This result was mainly driven by a significant trend towards a higher rate of TVR in patients with DM deferred based on FFR values compared to diabetic patients deferred based on iFR values (10 [6.4%] vs 0 [0%]), a result that did not achieve statistical significance (P = .065). This trend towards a lower rate of TVR in iFR-deferred vessels was not seen in non-DM patients (14 [5.1%] vs 2 [2.0%], P = .244) (figure 3).

Figure 3. Target vessel revascularization based on the technique used to defer revascularization at the 4-years follow-up. iFR, instantaneous wavefree ratio; FFR, fractional flow reserve.

DISCUSSION

The main findings of this study are: a) patients with DM had high rates of MACE. However, deferring the revascularization of intermediate stenoses in patients with DM based on the physiological assessment results with pressure guidewires is safe regarding the risk of TVR or target vessel myocardial infarction with a similar rate of events at the long-term follow-up compared to that seen in non-diabetic patients; b) both the FFR and the iFR can be used safely to defer intermediate stenosis in diabetic patients. c) there was a trend towards a higher rate of TVR in diabetic patients deffered based on FFR values.

Clinical outcomes based on the presence of diabetes mellitus

The use of coronary physiology to guide revascularization improves patient outcomes compared to angiographic assessment.3,6,7,13 Currently both the FFR and the iFR have a class IA recommendation in the clinical practice guidelines regarding revascularization for the functional assessment of coronary stenoses.1

Diabetic patients are a high-risk population with a more aggressive and accelerated atherosclerosis compared to non-diabetic patients. In the PARADIGM (Progression of atherosclerotic plaque determined by computed tomographic angiography imaging) study, the presence of DM was an independent risk factor for plaque progression.14 In a pooled analysis of 5 intravascular ultrasound trials, Nicholls SJ et al. found that patients with DM had a greater percent atheroma volume and a more rapid progression.15

Around 25% of the patients enrolled in pivotal studies that proved the effectiveness of the FFR and the iFR had DM.3,4,6,16,17 The safety of physiology-guided revascularization deferral in the DM setting has not been specifically assessed in randomized clinical trials. On the other hand, the results of the few non-randomized studies that have evaluated physiology-guided management in diabetics show conflicting results.18,19

Domínguez-Franco et al. analyzed the prognostic safety of the FFR in diabetics. Although, their results are consistent with ours in the sense that no differences were found in the TVR at the long-term follow-up after revascularization deferral in DM vs non-DM patients, the applicability and strength of that study is limited by its small sample size (136 patients, 144 lesions). Also, the use of a FFR cut-off value for the decision-making process was 0.75 while in contemporary practice cut-off values of 0.80 are often used.18

Recently, Kennedy et al. analyzed 250 patients (128 DM, and 122 non-DM patients) and found that DM was associated with a higher rate of failed deferred stenoses (18.1% vs 7.5%, P ≤ .01, Cox regression-adjusted (HR, 3.65; 95%CI, 1.40-9.53, P < .01), and target lesion revascularization of the deferred lesion (17.2% vs 7.5%; HR, 3.52; 95%CI, 1.34-9.30; P = .01). Nevertheless, and consistent with our results, no significant differences in the rate of target vessel myocardial infarction were seen (6.1% vs 2.0%; HR, 3.34; 95%CI, 0.64-17.30; P = 0.15).19 The TLR reported in the former study is much higher than the one seen in our population and the one reported by former studies (eg, in the FAME study the 2-year rate of TLR was 3.2% in FFR-negative lesions).2 These differences can be associated with the characteristics of concomitant medical therapy, which was not specified and may affect the evolution of patients with DM critically. In our study population most patients received optimal medical therapy with over 93% receiving statins while the former study did not specify the medical treatment used. Another important factor can be the percentage of insulin-treated patients with DM (42% in the former study vs 24% in our population). In a different study the same authors found that insulin therapy was a predictive factor of deferred lesion failure in patients with FFR values > 0.80.20 Differences in the risk profile of the populations may, therefore, explain the different results obtained. Our study, with a larger sample size, proves that compared to non-diabetics deferring the revascularization of intermediate stenoses in diabetic patients is safe, and with no differences in TVR at the follow-up. Another study with similar results was the one conducted by Van Belle et al. who saw that the FFR is an important tool to redefine the severity of stenosis in patients with DM with good results at 1 year in deferred patients (HR, 0.77; 95%CI, 0.47-1.25; P = .29; reclassified vs non-reclassified patients with DM).21

Clinical outcomes based on the physiological index used to defer revascularization

Our results suggest that both the FFR and the iFR can be used safely to defer intermediate stenoses in patients with DM. Our findings regarding the low rates of MACE at the follow-up are consistent with the sub-analysis of patients with DM from the DEFINE-FLAIR trial compared to the 1-year follow-up.22 Interestingly enough, we found a trend towards a higher rate of TVR in diabetics deffered with the FFR compared to the iFR. This can be associated with the presence of microvascular dysfunction in diabetic patients, and with the better correlation of iFR with indices that assess microcirculation like coronary flow reserve (CFR). One study evaluated the performance of the iFR and the FFR against invasive CFR in 216 stenoses to find a significantly stronger correlation and a higher diagnostic performance for the iFR (iFR area under the ROC curve, 0.82 vs FFR area under the ROC curve, 0.72; P < .001, for a coronary flow velocity reserve of 2).23 Cook et al. evaluated 567 vessels with sensor-tipped pressure and Doppler ultrasound guidewires and found that with discordant FFR–/iFR+ , the hyperemic flow velocity and the CFR were similar to the FFR+/iFR+ group (P > .05). However, with discordant FFR+/iFR–, the hyperemic flow velocity and the CFR were similar to both the FFR–/iFR– and the coronary unobstructed groups (P > .05).24 These findings may potentially explain the lower performance of FFR in the presence of microvascular dysfunction, and the tendency we found towards a higher TVR in diabetic patients deferred with FFR. Interestingly enough, this tendency was not found in non-DM patients, which supports the hypothesis of microvascular compromise as one of the potential causes for the differences observed between the 2 indices.

Limitations

This study has several limitations. First, this is a single-center observational, retrospective, non-randomized study. The results should be analyzed with caution and can only be interpreted as hypothesis-generating given the small sample size that limits the study statistical power. There were more patients evaluated with the FFR compared to the iFR, which may have influenced the results. Neither clinicians nor patients were blinded to the physiological results, which may have influenced future decisions on revascularization. Most patients had a single deferred vessel, meaning that extrapolation of this data to patients with multivessel disease is complex. Finally, microvascular dysfunction was not evaluated in this population, and the actual impact on the results cannot be determined.

CONCLUSIONS

Deferring the revascularization of intermediate stenoses in patients with DM based on the FFR or the iFR is safe regarding the risk of TVR or target vessel myocardial infarction, with a similar rate of these events at the long-term follow-up compared to the rate seen in non-diabetic patients.

FUNDING

None whatsoever.

AUTHORS’ CONTRIBUTIONS

A.F. Castro-Mejía, and A. Travieso-González contributed to the study idea, design, acquisition, analysis, and interpretation of data, and writing of the article, M.J. Pérez-Vizcayno contributed to both the analysis and interpretation of data, H. Mejía-Rentería, I.J. Núñez-Gil, P. Salinas, L. Nombela-Franco, P. Jiménez-Quevedo, A. Fernández-Ortiz, and C. Macaya contributed to the writing of the article, and made a critical review of its intellectual content. J. Escaned, and N. Gonzalo contributed to the writing of the article, made a critical review of its intellectual content, and gave their final approval to the version that would eventually be published.

CONFLICTS OF INTEREST

I.J Núñez-Gil is a consultant for Aztraseneca. P. Salinas received speaker fees from Boston Scientific, Terumo, Alvinedica, and Biomenco. L. Nombela-Franco has served as a proctor for Abbott, and received speaker fees from Edwards Lifesciences Inc. A. Fernández-Ortiz is a speaker at the educational events of Medtronic, Biotronik, Biosensor, and Bayer. J. Escaned is a speaker and consultant for Abbott, Boston Scientific, and Philips, and received personal fees from Philips Volcano, Boston Scientific, and Abbott/St. Jude Medical outside the submitted work. N. Gonzalo is a speaker at educational events for Abbott, and Boston Scientific. The remaining authors declared no conflicts of interest.

 

 

REFERENCES

INTRODUCTION

Distal embolization and slow coronary flow often limit the success of primary percutaneous coronary angioplasty (pPCI). In 25% to 50% of the cases, despite satisfactory flow restoration, poor microvascular reperfusion can be seen, which leads to worse prognoses.1 This is a field of ongoing discussion because strategies that initially showed positive results have later been questioned like direct stenting,2 thrombus aspiration,3,4 and the administration of beta-blockers,5 and IIB-IIIA inhibitors.6

It has been confirmed that aggressive balloon dilatation with a high balloon-to-artery ratio may favor the presence of no-reflow and it has been speculated that the deflation speed of the stent delivery system may impact the results too, although the information available on this regard is scarce.

No-reflow may be due to different pathophysiological factors such as distal embolization, ischemia-reperfusion injury, and the susceptibility of coronary microcirculation to injury.7,8 Rapid stent balloon deflation may trigger the so-called siphon effect and rapid changes in coronary hemodynamics that can be associated with distal embolization, and microcirculatory dysfunction.9 As part of a published report, the investigators built an in vitro experimental study and combined it with a computer model to eventually find that the wall shear stress due to the different balloon deflation strategies used triggered differences in the flow final velocity as well.

Our objective is to analyze the impact of the deflation speed of the stent delivery system on myocardial blush (MB), and the ST-segment resolution (STR) in the acute phase, as well as the prognosis and ejection fraction at the 12-month follow-up.

METHODS

Patients

A randomized, parallel, single-center study was conducted with a 24-hour program of pPCI including 440 000 patients. Recruitment was carried out by convenience sampling and eligible patients were all consecutive subjects with ST-segment elevation myocardial infarction (STEMI) referred to receive a pPCI who had a culprit lesion eligible for direct stenting. Patients should have ST-segment elevations ≥ 0.1 mV in 2 contiguous leads or new left bundle branch block.

Exclusion criteria were contraindications to acetylsalicylic acid, clopidogrel or IIB-IIIA inhibitors, impossibility to complete the follow-up, life expectancy < 12 months, lesion not amenable to direct stenting, culprit lesions located at grafts or in-stent thrombosis, and previous oral anticoagulation.

After performing the coronary angiography, the patients who met the inclusion criteria and had no exclusion criteria gave their initial oral consent and were allocated by simple randomization through a computer-generated list that would create individual codes. These codes were inserted one by one in identical envelopes—prepared by personnel not involved in the study—that were thick enough so the codes could not be seen. All patients were asked to confirm their participation by giving their written informed consent within 24 hours. The study protocol was designed in full compliance with the ethical guidelines of the 1975 Declaration of Helsinki as shown in a prior approval granted by the center human research committee.

Parallel groups were created by a) direct stenting with fast deflation of the stent delivery system after 20 seconds of balloon inflation (group 1), or b) direct stenting with slow deflation at 1 atm/second after the same period of inflation (group 2).

Procedure

Patients and outcome evaluators were blind to the procedure. To minimize variability and any potential confounders the protocol was strict and included the administration of 250 mg of acetylsalicylic acid followed by 600 mg of clopidogrel at the first medical contact (according to the myocardial infarction protocol of our unit), 70 mg/kg of IV heparin, and IV abciximab or tirofiban at the beginning of the procedure for a 12-hour administration course. Manual thrombectomy and posdilatation of the stent were performed systematically, but implantation of a second stent was not allowed per protocol. Intention-to-treat and per protocol analyses were performed. The former dictated the main analysis. The volume of contrast per injection was 6 mL administered for 3 seconds into the left main coronary artery followed by 4 mL administered for 2 seconds into the right coronary artery using the ACIST device (ACIST Medical Systems Inc., United States). Intracoronary nitroglycerine (100 µg to 200 µg) was administered before the final injection to assess MB. Myocardial blush was studied in the right anterior oblique 20-degree projection with 20-degree caudal angulation, and in the left anterior oblique 45-degree projection with 20-degree cranial angulation regarding the left main coronary artery, and in the anteroposterior projection with 20-degree cranial angulation regarding the right coronary artery. Recordings were acquired at 30 images/second without image magnification with a prolonged duration until the venous phase of the myocardial circulation was completed.

Within the first 30 minutes upon arrival to the coronary care unit, patients underwent a 12-lead electrocardiogram and blood samples were obtained for troponin I assessment 6 and 24 hours after the procedure, as well as additional measurements until a reduction in the levels reported was confirmed.

Optimal medical management according to guidelines was recommended with statins, beta-blockers, or renin-angiotensin system blockers. Also, dual antiplatelet therapy was indicated for 12 months. Switching to ticagrelor during admission was also recommended in the absence of significant risk of bleeding.

Outcomes

The 2 primary endpoints were how the deflation speed of the stent delivery system impacted MB at the end of the procedure, and the STR. The final MB was analyzed blindly by an external core laboratory in a different region and the variable analyzed was the percentage of MB grade ≥ 2 vs < 2 between both groups by visual assessment. Two interventional cardiologists with > 10 years of experience grading MBs10 were involved in the evaluation and, in case of disagreement, a third opinion was requested. The STR was analyzed by evaluators not involved in the study who were blind to the procedure. The J-point was manually identified with respect to the nearest 0.5 mm in all leads except in the aVR lead. Using the TP segment as the isoelectric baseline interval, the extent of the ST-segment elevation with respect to the nearest 0.05 mV was measured 80 ms after the J-point. The STR was estimated by a reduction in the sum of the ST-segment elevation in all leads except in the aVR from the baseline ECG compared to the ECG performed upon arrival at the coronary care unit. The variable was a binary outcome, the ≥ 70% resolution of the sum of millimeters of ST-elevation between both recordings.

The secondary endpoints were: a) size of the myocardial damage comparing the maximum levels of troponin I; b) ejection fraction at discharge; c) ejection fraction at 12 months; d) all-cause mortality rate at 12 months; and e) 12-month cardiovascular mortality rate.

Definitions

Angiographic thrombus burden was defined according to Sianos’ classification11 while collateral supply was defined according to Rentrop classification.12

Quantitative coronary angiography

The Medis Suite XA system (Medis Medical Imaging, Israel) was used for the analysis according to the experts’ standards.13 Lesion length was measured once the vessel flow had been restored after thrombectomy. The diameter parameters were taken at the end of the procedure after the stent was deployed due to the difficulties reported while performing analyses in thrombotic vessels. The following data were used: reference vessel diameter (the average lumen diameter assumed without atherosclerotic disease), minimal lumen diameter, postoperative stenosis, and the stent-to-artery ratio.

Sample size calculations

Based on a primary endpoint of STR of 50% in the control group14,15 and an increase up to 62.5% in the procedural group following, the principle of minimum clinically significant difference between treatments of 25%,16 and a dropout rate of 10%, 420 patients, 210 per group, were needed.

Interim analysis

Given the uncertainty of the results and the lack of data available on the medical literature, an interim futility analysis was planned after recruiting 50% of the sample size.

Statistical analysis

Quantitative variables with normal distribution were expressed as means and standard deviation, and those without a normal distribution as median and interquartile range. Categorical variables were expressed as absolute values and percentages. The mean comparison was carried out using the Student t test in normal distribution or the Mann-Whitney U test when that assumption was not met. The chi-square test or Fisher’s exact test were used to compare proportions. Two-tailed tests were used to analyze all studies. P values ≤ .05 were considered statistically significant. A logistic regression analysis was performed to adjust for possible imbalances and measure how the deflation speed rate of the stent delivery system impacted each of the 2 primary endpoints. The variables that met the 2 criteria of a reasonable association with the outcomes and P values < .20 in the univariate analysis were tested in the multivariate analysis. The calculations were performed using the SPSS 27.0.0.0 statistical software (IBM Corp, United States).

RESULTS

Baseline

From December 2016 through February 2019 a total of 447 patients were referred to our cath lab with a diagnosis of STEMI (figure 1, flow diagram). A total of 237 (53%) were not eligible for randomization and the remaining 210 (47%) were allocated to fast (103, 49%) or slow balloon deflation (107, 51%). The initially calculated sample size was 420 patients but, after an interim analysis with 50% of the sample recruited, the study was terminated early due to futility. There was 1 protocol violation in the first group and 4 in the second group. The intention-to-treat analysis is seen in this section and the per protocol analysis on tables 3 to 5 of the supplementary data. The baseline and procedural characteristics of the study cohort are shown on table 1 and table 2. There were no statistical differences between both groups although, despite the randomization process, there was a non-significant trend towards a larger vessel diameter in the slow deflation group. All cases were performed with 6-Fr guiding catheters.

Figure 1. Study flow-chart. ECG, electrocardiogram; PCI, percutaneous coronary intervention.

 

Table 1. Baseline clinical characteristics

	Fast deflation N = 103	Slow deflation N = 107	P
Age	59.73 (10.56)	59.33 (10.71)	.78
Sex (female)	26 (25.2)	20 (18.7)	.25
Diabetes	14 (13.6)	21 (19.6)	.24
Hypertension	40 (38.9)	48 (44.8)	.37
Hypercholesterolemia	37 (35.9)	45 (42.1)	.36
Smoking	65 (63.1)	71 (66.3)	.62
Previous myocardial infarction	4 (3.9)	6 (5.6)	.75
Previous percutaneous coronary intervention	3 (2.9)	4 (3.7)	1.00
Previous coronary artery bypass graft	0 (0)	1 (0.1)	1.00
Previous stroke	1 (0.1)	0 (0.0)	.49
Creatinine clearance levels < 60 mL/min	14 (13.6)	22 (20.5)	.18
Blood pressure at admission	123.4 (30.8)	129.6 (28)	.13
Shock	4 (3.9)	1 (0.09)	.21
Radial access	103 (100)	105 (98.1)	.50
Number of diseased vessels	1.38 (0.61)	1.45(0.66)	.42
Total ischemic time	192 (125-295)	169 (120-260)	.21
First medical visit to balloon time	87 (66-130)	80 (65-114)	.22
ST elevation before procedure (mm)	11.40 (6.74)	12.63 (8.06)	.24
Quantitative variables with normal distribution are expressed as means and standard deviation (SD), variables with non-normal distribution as median and interquartile range, and categorical variables are expressed as absolute values and percentages.

 

Table 2. Characteristics of the procedure

	Fast deflation N = 103	Slow deflation N = 107	P
Vessel			.60
Left anterior descending coronary artert	44 (42.7)	40 (37.4)
Left circumflex artery	13 (12.6)	18 (16.8)
Right coronary artery	46 (44.7)	49 (45.8)
Preoperative TIMI ≥ grade 2 flowa	10 (9.7)	17 (15.9)	.21
Rentrop ≥ 2	15 (14.6)	19 (17.8)	.53
Thrombus grade score ≥ 4	46 (44.6)	50 (46.7)	.76
Drug-eluting stent	100 (97.1)	101 (94.4)	.50
Percent diameter stenosis	99.28 (3.43)	98.89 (6.48)	.58
RVDb	2.74 (0.42)	2.86 (0.47)	.07
Lesion length	14.07 (5.94)	13.44 (4.71)	.39
Stent diameter	3.23 (0.47)	3.32 (0.57)	.17
Maximum inflation pressure	14.68 (1.48)	14.77 (1.69)	.67
MLDc	2.89 (0.38)	3.00 (0.49)	.06
Minimum lumen diameter	2.63 (0.39)	2.67 (0.48)	.48
Postoperative stenosis	8.92 (4.75)	11.20 (6.25)	.01
Stent-to-artery ratio	1.05 (0.07)	1.05 (0.08)	.95
Quantitative variables with normal distribution are expressed as means and standard deviation (SD), variables with non-normal distribution as median and interquartile range, and categorical variables are expressed as absolute values and percentages. a TIMI, Thrombolysis in Myocardial Infarction risk score. b RVD, reference vessel diameter after the procedure. c MLD, maximum lumen diameter after the procedure.

 

Table 3. Results

	Fast deflation N = 103	Slow deflation N = 107	P
Myocardial blush ≥ 2	77 (74.7)	79 (75.2)	.93
Postoperative ST-segment elevation (mm)	4.26 (5.19)	4.03 (4.69)	.73
ST-segment elevation resolution (mm)	7.03 (6.99)	8.56 (8.11)	.15
Percentage of resolution (%)	64.97 (33.35)	65.40 (34.69)	.92
Resolution ≥ 70 %	54 (53.4)	59 (55.6)	.75
TIMI grade flow after the procedure			.38
0	1	0
1	0	1
2	5	9
3	97	97
Maximum troponin-I levels	47.84 (14-129)	72 (29.7-144.75)	.14
Ejection fraction at discharge	53.9 (8.58)	54.62 (8.71)	.55
Ejection fraction at 12 months	57.43 (8.20)	57.75 (6.48)	.76
In-hospital mortality rate	1 (0.9)	2 (1.8)	1.00
Overall mortality rate at 12 months	3 (2.9)	3 (2.8)	1.00
Cardiovascular mortality rate at 12 months	2 (1.9)	3 (2.8)	1.00
Myocardial infarction	1 (0.9)	1 (0.9)	1.00
Target vessel revascularization	0	1 (0.9)	1.00
Quantitative variables with normal distribution are expressed as means and standard deviation (SD), variables with non-normal distribution as median and interquartile range, and categorical variables are expressed as absolute values and percentages. TIMI, Thrombolysis in Myocardial Infarction risk score.

 

Table 4. Predictors of myocardial blush ≥ 2 and ST-segment resolution

	OR	95%CI	P
Predictors of myocardial blush ≥ 2
Systolic blood pressure at admission	1.02	1.02-1.03	.011
Creatinine clearance levels <60 mL/min	0.29	0.13-0.66	.003
Postoperative maximum lumen diameter	3.08	1.24-7.63	.015
Hypertension	0.52	0.26-1.06	.074
Predictors of ST-segment resolution
Diabetes	0.16	0.06-0.43	< .001
Previous myocardial infarction	13.54	1.47-124.91	.022
Left anterior descending coronary artery	0.46	0.24-0.91	.025
Preoperative TIMI grade flow ≥ 2	3.95	1.36-11.46	.011
Postoperative TIMI grade 3 flow	7.10	1.76-28.68	.006
Rentrop grade ≥ 2 collateral circulation	0.31	0.13-0.75	.010
Quantitative variables with normal distribution are expressed as means and standard deviation (SD), variables with non-normal distribution as median and interquartile range, and categorical variables are expressed as absolute values and percentages. 95%CI, 95% confidence interval; OR, odds ratio; TIMI, Thrombolysis in Myocardial Infarction risk score.

 

Endpoints

The primary endpoint, MB grade ≥ 2compared to < 2, occurred in 77 (74.7%) vs 79 (75.2%), P = .93, of the patients, and STR ≥ 70% in 54 (53.9%) vs 59 (55.5%), P = .75, of the patients from the rapid and slow deflation groups, respectively. Also, there were no differences in any of the secondary endpoints regarding the size of myocardial damage, the ejection fraction at discharge, the ejection fraction at 12 months, the overall mortality rate at 12 months or in the cardiovascular mortality rate at 12 months (table 3).

Predictors of myocardial blush

The univariate analysis was performed with the variables shown on table 1 of the supplementary data. The variables age, creatinine clearance levels < 60 mL/min, postoperative maximum lumen diameter, past medical history of hypertension, systolic blood pressure at admission, Rentrop grade ≥ 2 collateral circulation, and the first medical contact to balloon time were tested using a logistic regression model. Systolic blood pressure at admission, creatinine clearance levels < 60 mL/min, and the postoperative maximum lumen diameter were predictors of blush ≥ 2 while in the final model hypertension remained with P values = .074 (table 4). The predictive power was moderate with an area under the ROC curve of 0.71 (0.63-0.80) (figure 2).

Figure 2. Receiver operating characteristic curve of the logistic regression model for myocardial blush prediction.

 

Predictors of ST-segment resolution ≥ 70%

The univariate analysis was performed with the variables listed on table 2 of the supplementary data. The variables tested in the multivariate analysis were sex, diabetes, hypercholesterolemia, smoking, shock, left anterior descending coronary artery, previous myocardial infarction, preoperative TIMI grade ≥ 2 flow, postoperative TIMI grade 3 flow, and Rentrop grade ≥ 2 collateral circulation, number of millimeters of ST elevation before the procedure, and creatinine clearance levels < 60 mL/min. The logistic regression model included diabetes, previous myocardial infarction, left anterior descending coronary artery, preoperative TIMI grade ≥ 2 flow, postoperative TIMI grade 3 flow, and Rentrop grade ≥ 2 collateral circulation as predictors of ST-segment resolution ≥ 70% (table 4). The area under the ROC curve was 0.75 (0.68-0.82) (figure 3).

Figure 3. Receiver operating characteristic curve of the logistic regression model for ST-segment resolution.

 

Per protocol analysis

Protocol deviation was seen in 5 patients. In the rapid deflation group 2 stents were needed in 1 patient. In the slow deflation group 3 patients received 2 stents followed by 1 postdilatation (figure 1). Tables 3, 4 and 5 of the supplementary data show the per protocol analysis without any significant differences compared to the intention-to-treat analysis.

Missing values

In 2 patients from the slow deflation group, the quality of the angiogram did not allow us to perform a proper analysis. Regarding the electrocardiogram, suboptimal quality was recorded in 2 patients from the rapid deflation group and in 1 patient from the slow deflation group. All of them may be considered as missing values completely at random, which means that the randomization balance was never affected.

DISCUSSION

In this randomized study we assessed how the deflation speed of the stent delivery system impacted myocardial blush ≥ 2, and ST-segment resolution ≥ 70%. The most important findings are: a) the study was stopped with 50% of the predefined sample sized due to futility and neither MB nor STR were modified by the intervention; b) no differences were seen in the size of myocardial damage, ejection fraction at 12 months and discharge or in the all-cause and 12-month cardiovascular mortality rates; c) systolic blood pressure at admission, creatinine clearance levels < 60 mL/min, and postoperative maximum lumen diameter played a role in MB while the past medical history of hypertension would have probably been included in the final model if the sample size would have been larger; and d) STR was influenced by diabetes, previous myocardial infarction, left anterior descending coronary artery, preoperative TIMI grade ≥ 2 flow, postoperative TIMI grade 3 flow, and Rentrop grade ≥ 2 collateral circulation.

The data available on the medical literature on this research topic is significantly scarce and, to our knowledge, only 1 group has provided information. Gu et al.17 also studied the association of balloon deflation during stent deployment with coronary flow and clinical outcomes regarding pPCI in a series of 211 patients. They found that slow deflation led to favorable coronary flow and infarct size compared to conventional rapid deflation. These contradictory results may be justified by the remarkable differences seen between both cohorts. Former studies have reported on the role of balloon inflation,18 thrombectomy,19,20 and IIB-IIIA inhibition21 in the management of MB. In our series, we designed a strict protocol to control these potential confounders, which is why pre- and postdilatation was not allowed, and both thrombus aspiration and IIB-IIIA inhibitors were essential components of the procedure. The study conducted by Gu et al. allowed both pre- and postdilatation while the use of thrombectomy, and IIB-IIIA inhibitors was left to the operator’s discretion. Indeed, predilatation was performed in > 80% of the patients from both groups, postdilatation in roughly 40%, thrombus aspiration in only 20%, and IIB-IIIA inhibitors were administered in 70% of the patients. Undoubtedly, the approach conducted by Gu et al. favored external validity although, in our opinion, the influence of these 4 factors may have influenced the results deeply, mainly when no adjustment was performed through a multivariate analysis. Finally, although closely related, the TIMI frame count and MB are not the same endpoint, and the ST-segment resolution was not assessed in the study conducted by Gu et al. Regarding the clinical endpoints, no differences were seen between the 2 strategies in any of the 2 studies.

As we mentioned, we were not able to show that the deflation speed of the stent delivery system impacted MB. In the multivariate analysis performed, blood pressure levels at admission, creatinine clearance levels, and the postoperative maximum lumen diameter were all predictors of MB while a past medical history of hypertension would have probably reached statistical significance with a larger sample size. Former reports have underlined how blood pressure impacts MB during the procedure.22 Also, patients with hypertension due to an increased microvascular resistance have shown an impaired flow.22 In addition, it has been reported that the adverse event of renal function regarding cardiovascular events may be mediated by an increased microvascular resistance.23 Time to treatment has impacted MB in previous studies.24 In our cohort, there were significant differences in the univariate analysis, but in the last step of the multivariate analysis it was removed from the final model, although it would have probably been present with a larger sample size. However, in the comparison of our series with the aforementioned study, we tested the vessel size as a predictor of MB while this variable was not analyzed in Luca’s study, but it had played a role in previous cohorts.25

Consistent with this, the deflation speed of the stent delivery system did not seem to play a role in STR. We found up to 6 factors that proved its impact on the ST-segment resolution, most of them already described in former studies. As it leads to a lower ST-segment elevation, collateral circulation reduces the impact of pPCI in STR.26 Anterior infarctions with culprit lesion in the left anterior descending coronary artery also led to lower ST-segment recoveryies in previous cohorts.27-29 This was also seen with preoperative TIMI grade < 2 flow, and final TIMI grade flow < 3,14,27,28,30 and diabetes.14,28 In our series, previous myocardial infarction was a predictor of STR, although we found no explanation for this finding.

Limitations

The study was stopped in the interim analysis based on the criterion of futility. However, we do not expect the results of primary endpoints to have been any different with the whole sample size. We could have probably found more predictors and a higher predictive power of the MB and STR models, but this was not the endpoint of our study. The risk profile of the patients was low because the inclusion criteria of direct stenting, use of IIB-IIIA inhibitors, and thrombectomy focused the study on lesions more frequently associated with younger patients with a low bleeding risk and less calcification, which are features associated with better outcomes. This limits the external validity of the study because, as shown on figure 1, roughly 50% of the patients were ineligible to enter the study. This may have also played a role in the lack of differences seen between the study groups. However, as we have already explained, the purpose of our study was to avoid any confounders. Clopidogrel was the P2Y₁₂ inhibitor at the first medical visit according to the protocol of the regional myocardial infarction network of our area. This may also limit the external validity of the results. Myocardial blush was visually assessed and, although it was performed by 2 experienced operators, certain degree of subjectivity cannot be ruled out. The predictive power for both MB and STR was low, but it has also occurred in former series28 being the concordance between those factors described as moderate.31 Finally, we could not find any explanations for the role of previous myocardial infarction predicting STR as this factor was not present in former series.

CONCLUSIONS

In our series, the deflation speed of the stent delivery system in primary angioplasty did not change myocardial blush or ST-segment resolution and no influence was seen on the clinical outcomes, size of myocardial infarction assessed by biomarkers, and ejection fraction at discharge and after 12 months.

FUNDING

The study has been supported by a research grant from Abbott Laboratories.

AUTHORS’ CONTRIBUTIONS

B. Vega, J. M. Vegas, J. Rondan, E. Segovia, and Í. Lozano: design, data mining, manuscript drafting, and manuscript revision. A. Pérez de Prado, C. Cuellas-Ramon, M. López-Benito, T. Benito-González, and F. Hernández-Vázquez: blush measurements, and manuscript revision.

CONFLICTS OF INTEREST

The authors declared no conflict of interests whatsoever.

REFERENCES

INTRODUCTION

Assessing functional severity of coronary stenoses at left main coronary artery (LMCA) level through coronary angiography has serious limitations.1 To treat angiographically intermediate stenoses (25% to 60% diameter) the use of invasive (ultrasound or optical coherence tomography) or functional imaging modalities (determining fractional flow reserve [FFR] to indicate the need for revascularization) has been proposed.2 Patients with LMCA stenosis have traditionally been excluded from randomized clinical trials that assessed the prognostic capabilities of the functional assessment of coronary stenoses through the use of FFR.3-5 The use of FFR to assess LMCA stenoses is backed by a limited number of non-randomized clinical trials that confirmed that FFR values > 0.80 is associated with a low risk of events if no revascularization is performed in patients with intermediate LMCA stenoses.6

The instantaneous wave-free ratio (iFR) is a new, easier-to-use, and cost-effective invasive index to assess the coronary function compared to FFR since there is no need to induce maximum coronary hyperemia to estimate it.7 Although a non-inferior prognostic value of iFR compared to the FFR has recently been confirmed in patients with intermediate lesions in 2 large trials, the presence of LMCA lesions was largely anecdotal or inexistent in both indices.8,9 However, a non-randomized clinical trial has been published with a similar design to those previously conducted with the FFR that provides encouraging data on the value of iFR in the decision-making process regarding the LMCA. However, in such trial, the FFR—the most widely used index to assess intermediate LMCA stenoses—was not determined at the same time, which means that the results of this registry cannot be put into context.10 Also, there are signs that the location of the LMCA lesion is a predictor of worse concordance between both indices.11

Proving the clinical safety of iFR in patients with intermediate LMCA lesions would have a major clinical impact and justify its systematic use in the decision-making process regarding the management of these high-risk patients.

The objective of this study is to assess the concordance between 2 physiological indices—the FFR and the iFR—in the assessment of intermediate LMCA lesions. Also, to validate prospectively the clinical safety profile of a revascularization strategy based on an iFR cut-off value of 0.89.

METHODS

Study design

National, prospective, observational, and multicenter registry including 300 consecutive patients with intermediate LMCA lesions (25% to 60% angiographic stenosis). A study will be conducted in all patients using intracoronary guidewire pressures. Also, both the FFR and the iFR values will be determined distal to the LMCA. Per protocol it is advised that the indication for revascularization should be decided based on the result of the iFR in such a way that:

 

 

Patients whose management is not consistent with what the iFR value recommends will not be addressed for the strategy safety analysis, and clinical outcomes will be assessed separately.

 

Figure 1 shows the decision-making algorithm based on FFR and iFR results. IVUS is indicated in controversial cases, and recommended in the remaining cases to determine the correlation between the MLA and the iFR.

Figure 1. Decision-making algorithm based on the FFR and iFR results. DES, drug-eluting stent; FFR, fractional flow reserve; iFR, instantaneous wave-free ratio; IV, intravenous; IVUS, intravascular ultrasound; LMCA, left main coronary artery; MACE, major adverse cardiovascular events, MLA, minimum lumen area.

 

In patients eligible for percutaneous treatment, IVUS is highly recommended, and its utility will be assessed prospectively during the planning and optimization of the procedure.

Clinical follow-up is advised from 12 months to 5 years to determine the prognostic primary endpoint by assessing a composite endpoint of cardiovascular death, LMCA lesion-related non-fatal infarction or need for LMCA revascularization at the 12-months and 5-year follow-up.

Notifications

The study has been approved by the reference ethics committee and notified to the local ethics committee of all participant centers. The study has been registered in Clinicaltrials.gov with registration number NCT03767621. Devices with CE marking have only been used, and only for the indications already approved. The study observes the principles established by the Declaration of Helsinki. All patients gave their prior written informed consent to participate in the study.

Study population

Patients with suspected or confirmed ischemic heart disease on whom a coronary angiography is performed that detects intermediate angiographic LMCA stenoses (between 25% and 60%). Also, patients in whom intracoronary pressure guidewires are used to determine the iFR and the FFR in the LMCA lesion to decide on the indication for myocardial revascularization—whether percutaneous with a DES or surgical—based on the indication considered more appropriate.

Inclusion and exclusion criteria are shown on table 1. In cases of severe lesions at left anterior descending coronary artery or left circumflex artery level, the patient will not be included in the study unless the LMCA lesion is assessed after the percutaneous treatment of these lesions while taking into account that, if the LMCA lesion is significant, treatment will be percutaneous.

 

Table 1. Inclusion and exclusion criteria of the iLITRO-EPIC-07 trial

Inclusion criteria

Patients with intermediate LMCA lesions (25% to 60% angiographic stenosis on visual estimations) eligible for a pressure guidewire study to determine the iFR

Patients aged ≥ 18 years

Patients capable of giving their informed consent

Exclusion criteria

Patients with an indication for coronary artery bypass graft regardless of the significance of the LMCA lesion

Patients with LMCA lesions showing ulceration, dissection or thrombus

Patients with lesions in a previously non-dysfunctional arterial or venous graft in the territory irrigated by the LMCA (protected LMCA)

Patients with acute coronary syndrome with potentially culprit lesion in the LMCA

Patients incapable of giving their informed consent

iFR, instantaneous wave-free ratio; LMCA, left main coronary artery.

 

Study endpoints

The iLITRO-EPIC 07 trial has 2 primary endpoints:

 

 

Secondary endpoints are to determine the correlation between the iFR value in these lesions and the MLA determined by the IVUS and the utility of IVUS for the planning and optimization of LMCA lesions (table 2).

 

Table 2. Secondary endpoints of the iLITRO-EPIC-07 trial

Correlation between the assessment obtained through pressure guidewire (iFR) and the minimum lumen area measured through IVUS

Role of IVUS in the planning of treatment in the subgroup of patients treated with percutaneous therapy

Role of IVUS in the optimization of treatment in the subgroup of patients treated with percutaneous therapy

All-cause mortality at 12 months and 5 years

Cardiovascular death at 12 months and 5 years

Non-fatal infarction at 12 months and 5 years

LMCA lesion-related non-fatal infarction at 12 months and 5 years

Revascularization at 12 months and 5 years

Myocardial infarction associated with the revascularization of the LMCA (whether percutaneous or surgical)

Thrombosis of 1 or several stents in the LMCA at 12 months and 5 years

Restenosis of 1 or several stents in the LMCA at 12 months and 5 years

New target lesion revascularization in the LMCA (whether percutaneous or surgical) at 12 months and 5 years

iFR, instantaneous wave-free ratio; LMCA, left main coronary artery; IVUS: intravascular ultrasound.

 

Study procedure

 

Figure 2 shows the procedure methodology on a flowchart.

Figure 2. Study protocol and procedures. ACS, acute coronary syndrome; CABG, coronary artery bypass graft; FFR, fractional flow reserve; iFR, instantaneous wave-free ratio; IVUS, intravascular ultrasound; LAD, left anterior descending coronary artery; LCX, left circumflex artery; LMCA, left main coronary artery; MLA, minimum lumen area; PCI, percutaneous coronary intervention; QCA, quantitative coronary angiography.

 

Protocol to perform a study using a pressure guidewire

The patient is eligible for functional assessment in the presence of intermediate LMCA stenoses with visual estimations on the coronary angiography between 25% and 60%.

After catheterization using a guide catheter, at least, 200 µg of intracoronary nitroglycerin should be administered to keep coronary reactivity under control. Afterwards, the intracoronary guidewire should be advanced with the sensor placed in the ostium of the guide catheter; also, pressure curves should be brought back to normal for 5 to 10 heart beats. if the lesion has an ostial location, normalization will occur by removing the guide catheter from the coronary artery and placing the guidewire into the aorta. Afterwards, the guidewire should be removed from the catheter, and coronary catheterization performed to advance the guidewire.

The pressure guidewire should be advanced until, at least, 3 times the diameter of the vessel beyond the most distal stenosis to be able to measure the iFR according to the standard protocol.

After measuring the iFR, the guidewire should be removed with pressure curve monitorization until the inside of the guide catheter. At this point, the presence of the pressure calibration loss phenomenon (drifting) should be discarded. In case of overt drift (Pd/Pa measured on the catheter tip < 0.98 or > 1.02) measures should be taken again.

Afterwards, the FFR will be determined during hyperemia through the administration of adenosine in continuous IV infusion at doses ≥ 140 µg/kg/min for, at least, 2 minutes or an IV bolus of 0.4 mg of regadenoson.

After measuring the FFR, the guidewire should be removed with pressure curve monitorization until the inside of the guide catheter. At this point, the presence of drifting should be discarded. In case of overt drift (Pd/Pa measured on the catheter tip < 0.98 or > 1.02) measures should be taken again.

In case of discrepancy between the results of the FFR and the iFR (FFR ≤ 0.80 with iFR ≥ 0.90 or FFR ≥ 0.81 with iFR ≤ 0.89) IVUS will be performed, and the MLA determined. Revascularization will be indicated with MLAs < 6 mm2 based on the results from the LITRO trial.12

Protocol to conduct IVUS studies

IVUS studies will be mandatory if the FFR and the iFR disagree. In patients eligible for percutaneous treatment of their LMCA lesions, the IVUS is highly recommended to guide the procedure. In the remaining patients (when iFR-guided medical therapy or surgical revascularization is decided) the IVUS is recommended to establish the correlation between the iFR value and the MLA measured on the LMCA whenever possible. The IVUS system used can be mechanical or rotational with resolutions between 20 MHz and 60 MHz.

An 0.014 in intracoronary guidewire will be advanced to perform the IVUS study (it can be the same pressure guidewire used to determine the iFR) towards the left anterior descending or left circumflex coronary arteries. After the administration of 200 µg of intracoronary nitroglycerin, the IVUS catheter will be advanced distal to the LMCA bifurcation. Afterwards, the catheter will be manual or automatically removed until the ascending aorta. It is essential that the guide catheter should remain outside the coronary artery to study the left main coronary artery entirely including its ostial region. The catheter will be placed in the left anterior descending coronary artery (preferably) or left circumflex artery or both (to conduct 2 studies with MLA determination from these positions and eventually pick the one with the lowest values).

In cases of catheter backward jump, even on manual mode (with calcified angulation) it is recommended to move the catheter forward from the aorta to acquire images of the region of interest that had not been properly assessed.

Technical aspects of the assessment of left main coronary artery lesions through fractional flow reserve

The study of LMCA lesions using pressure guidewires has some particularities that should be addressed when conducting the study.

Location of the lesion

A total of 3 different possible lesion locations can be anatomically distinguished on the LMCA depending on whether there is damage to the ostium, body or distal portion (bifurcation). The location of the lesion inside the LMCA has implications when conducting the study with the pressure guidewire. When the lesion is found in the ostium or the body, catheterization should be coaxial. Non-coaxial catheterization involves contact of the catheter lumen with the vessel wall to the extent that it can dampen the aortic pressure and artificially elevate the value of the FFR. For this reason, non-selective catheterization is advised when equalizing or normalizing the catheter and guidewire pressures when the latter is placed distal to the lesion to measure the FFR during maximum hyperemia. When the lesion is found in the LMCA distal portion and there is damage to its origin and main branches, both the distal LMCA and each one of its branches should be treated as 1 functional unit regardless of the degree of damage to these branches. To estimate the FFR, measurements are taken from the left anterior descending and left circumflex coronary arteries. The LMCA lesion is considered functionally significantly when the measurements of either one of the 2 main vessels is < 0.80.

Induction of hyperemia

In the assessment of LMCA lesions the use of an intracoronary bolus of adenosine is ill-advised because, since the non-selective catheterization of the left coronary artery is required, part of the drugs administered never reach this coronary artery, which is why the induction of hyperemia can be suboptimal. For this reason, the IV administration of drugs whether adenosine (infusions of 140 µg/kg/min for, at least, 2 minutes) or regadenoson (doses of 0.4 mg in IV bolus) is advised.13

Presence of left anterior descending or left circumflex coronary artery lesions

The presence of 1 isolated LMCA lesion is not rare. A series of all-comers treated with diagnostic coronary angiography proved that, in patients with damage to the LMCA, only 9% had 1 single LMCA lesion, 17% had 1 LMCA lesion plus damage to 1 vessel, 35% had 1 LMCA lesion plus damage to 2 vessels, and 38% had LMCA disease plus damage to 3 vessels.14

Statistical analysis

Demographic, clinical, hemodynamic, and procedural data will be presented for the entire group. Continuous variables will be expressed as mean, and standard deviation (or if the distribution of the values do not follow a normal, as median, and interquartile range). Categorical variables will be expressed as frequencies and percentages. The data obtained will be studied using the unilateral analysis of variance (ANOVA) for the continuous variables, and Fisher’s exact test or the chi-square test for the categorical variables, when appropriate. When appropriate, non-parametric tests will be used with variables without a normal distribution or when normalization is not possible. The Kaplan-Meier survival curves will be presented for the previously specified criteria. The concordance analyses will be conducted using Cohen’s kappa coefficient. Also, sensitivity, specificity, positive and negative predictive values, and the area under the receiver operating characteristic (ROC) curve will be estimated.

Data curation and monitorization

Clinical, angiographic, physiological, and IVUS data will all be saved in a safe electronic CRD managed by Fundación EPIC, the promotor of the study. Clinical data at both the 12-month and 5-year follow-up, as well as the presence of cardiovascular events at the follow-up will also be saved in the same electronic CRD.

DISCUSSION

The iLITRO-EPIC 07 trial has a double primary endpoint: on the one hand, to establish the concordance between 2 intracoronary physiological indices, the FFR and the iFR, when assessing the severity of intermediate LMCA lesions; on the other hand, to study the use of a predetermined iFR value to indicate the revascularization of intermediate LMCA lesions with an up to 5-year clinical follow-up.

Left main coronary artery disease. Implications for the interventional cardiologist

Significant LMCA disease, understood as a stenosis in its greater diameter > 50%, is associated with a poor mid-term prognosis. Studies prior to coronary revascularization confirmed survival rates < 40% at the 4-year follow-up after diagnosis.15

The limitations of the angiographic assessment of the severity of LMCA lesions are well established.16-18 Before suggesting revascularization in a patient with LMCA lesions, in particular ostial lesions, it is important to know whether the lesion really needs to be revascularized, that is, whether it is hemodynamically significant. LMCA stenoses are found in between 4% to 9% of all diagnostic coronary angiographies.1 Due to their anatomical location, catheter-induced artifacts or to the severity of distal lesions, among other factors, interpreting LMCA lesions is associated with the highest intra- and inter-observer variability compared to lesions found in other parts of the coronary tree.16 When stenoses ≥ 50% were found in the CASS registry,19 a second observer confirmed that the stenosis was not significant in 19% of the cases.

Several former studies have confirmed that the prognosis of patients with functionally insignificant LMCA lesions is favorable.6 Also, that the surgical revascularization of hemodynamically insignificant lesions is associated with a high rate of early graft failure.20

The LITRO trial, led by the Spanish Society of Cardiology Working Group on Intracoronary Diagnostic Techniques, was a multicenter and prospective study. It proved that, in patients with angiographically intermediate LMCA lesions, the presence of a MLA ≥ 6 mm2 measured on the IVUS allows us to delay revascularization in a safely manner.12

Evidence to guide the revascularization of the left main coronary artery through functional assessment

To this date, no definitive data on the prognostic value of iFR measurements in intermediate LMCA stenoses have been published. The presence of a significant stenosis (> 70%) on the coronary angiography was an exclusion criteria in the DEFER, FAME, and FAME II clinical trials, as well as in the DEFINE FLAIR trial. Only the IFR SWEDEHEART trial included 30 patients with significant LMCA stenoses (1.6% of all the patients included).3-5,8,9 An observational and retrospective study of 314 patients confirmed that delaying the revascularization of the LMCA using a iFR cut-off value of 0.89 as the guide was safe at the 30-month clinical follow-up.10 However, in this observational registry the FFR, a widely validated index in the LMCA, was not obtained at the same time. This means that the results reported by this registry cannot be put into context and the concordance between both indices cannot be analyzed either.

The data available that support the use of the FFR in LMCA lesions come from several studies shown on table 1. The cut-off values used in these studies go from 0.75 to 0.80. In the study that has included, to this date, the highest number of patients with intermediate angiographic lesions, 213, only patients with FFR values < 0.80 were treated. However, in patients with higher values a conservative manage was used. No differences in the mortality or severe cardiovascular event rates were reported at the 5-year follow-up.6 Therefore, the reference FFR value for LMCA lesions, as well as the remaining lesions, is < 0.80.

A metanalysis that included data from 8 landmark studies found no differences in the primary endpoint of death, non-fatal myocardial infarction or revascularization. However, the need for revascularization was greater in the group on medical therapy: whether this was primarily due to the revascularization of the LMCA is still under discussion.21

A recent study that assessed the correlation between the FFR and the iFR values based on the location of the lesion studied revealed that such correlation was weaker when the lesion was found on the LMCA or in the proximal left anterior descending coronary artery compared to other locations. This was attributed to a greater amount of vessel-dependent myocardium in these proximal lesions. Taking the FFR value and an iFR cut-off value ≥ 0.89 as a reference, both the false positives (21.9%) and the false negatives (26.7%) were more evident when the lesion was found on the LMCA or the proximal left anterior descending coronary atery.11 Some studies have suggested that resting indices like the iFR could provide better measurements of coronary flow during hyperemia compared to the FFR.22,23 This means that using the FFR as the gold standard could be questionable in this setting. Also, the scientific evidence available indicates that the discrepancies seen between the iFR and the FFR are not associated with a worse prognosis.24 This means that the present study could clarify whether the iFR is associated with a weaker indication for revascularization in intermediate LMCA lesions with the exact same clinical safety compared to the FFR.

CONCLUSIONS

The iLITRO-EPIC 07 trial is the first prospective study to assess the concordance between the FFR and the iFR in intermediate LMCA lesions. Also, that it is safe to guide the indication for revascularization based on an iFR cut-off value of 0.89.

FUNDING

The promoter of the study, Fundación EPIC, has received an institutional research grant from Phillips Volcano (The Netherlands) to pay for the design and maintenance costs of the electronic CRD. Philips Volcano has not been involved in the design of the study or protocol whatsoever. Philips Volcano has not been involved in the development of the study whatsoever including recruitment, follow-up, data curation, result analysis and interpretation, writing or final approval of both the protocol and this manuscript. The authors are solely responsible for the study design, writing, edition, and final version of the manuscript.

AUTHORS’ CONTRIBUTIONS

All the authors are lead investigators of the iLITRO-EPIC07 trial at their corresponding working centers, collaborated in the writing of the study protocol, and in the recruitment of the patients. The manuscript was written by O. Rodríguez-Leor, J.M. de la Torre-Hernández, and A. Pérez de Prado; the remaining authors reviewed the manuscript.

CONFLICTs OF INTEREST

A. Pérez de Prado declared to have received fees from iVascular, Boston Scientific, Terumo, B. Braun, and Abbott Vascular. José M. de la Torre Hernández is the editor-in-chief of REC: Interventional Cardiology. F. Alfonso, and J. Sanchis are associate editors of REC: Interventional Cardiology; the journal’s editorial procedure to ensure impartial handling of the manuscript has been followed.

 

 

REFERENCES