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

INTRODUCTION

Coronary angiography (CA) is a key step in treatment of patients with non-ST-elevation acute myocardial infarction (NSTEMI). CA reduces mortality and the rates of new cardiovascular adverse events compared to the conservative approach.1^,2 Therefore, the current European clinical practice guidelines on the management of NSTEMI recommend an invasive strategy to treat these patients.1

The appropriate time to perform the CA in NSTEMI patients is still under discussion. Early CA (within the first 24 h after diagnosis) is still recommended in patients with high-risk NSTEMI defined as a GRACE score > 140. However, the potential benefit of this approach has not been completely established yet.3

The objective of our study was to assess the prognostic impact of an early CA (within the first 24 h after diagnosis) in patients NSTEMI compared to a delayed CA strategy (after 24 h).

METHODS

This is a retrospective, observational cohort study. From January 2014 to June 2016, data from 447 patients with NSTEMI admitted to a tertiary referral hospital who underwent an invasive coronary angiography were consecutively collected.

NSTEMI was defined according to the guidelines and all patients were treated following the recommendations established by these guidelines.1

Data from all the cases were included prospectively in a continuous multipurpose database. The collection of data included detailed past clinical histories, physical examinations, pulse oximetry measures, 12-lead electrocardiograms, continuous electrocardiogram monitoring, blood tests, echocardiographies, and CAs. The Global Registry of Acute Coronary Events (GRACE) and Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) scores were calculated for each patient.1

Patients were classified into 3 groups according to the time to CA (figure 1): catheterization within the first 24 h after diagnosis (group 1, n = 285 patients), 24 h to 72 h later (group 2, n = 102 patients) and after 72 h (group 3, n = 60 patients). The decision on when to perform the CA was made by the treating physician in each case. After being discharged from the hospital, the 12-month follow-up of patients was performed in a dedicated clinic.

Figure 1. Flowchart. CA, coronary angiography; NSTEMI, non-ST-elevation acute myocardial infarction.

The primary endpoints of our study were mortality and major adverse cardiovascular events (stroke, new acute coronary syndrome, new revascularization) during hospitalization and depending on the time to CA in patients with NSTEMI. The secondary endpoints were mortality and the rate of major cardiovascular events at the 1-year follow-up, and bleeding events according to the BARC criteria.4 We also analyzed the antiplatelet treatment prescribed at discharge and its correlation with MACE at follow-up.

Statistical analysis

Continuous variables are described as mean and standard deviation or median and interquartile range [IQR] when appropriate. The Kolmogorov-Smirnov test was used to assess the variables normal distribution. Regarding quantitative variables, the groups were compared using the 2-tailed Student t test or the Mann-Whitney U test when necessary. Categorical variables were expressed as frequency and percentage, and compared using the chi-square test or Fisher’s exact test when appropriate. No variable had losses > 15%.

A multivariate logistic regression analysis was performed to assess the potential impact of the CA timing on in-hospital mortality. The model included all variables that were statistically significant in the univariate analysis regarding mortality and time to CA. Adjusted odds ratios (OR) with 95% confidence intervals (95%CI) were calculated for each variable. Regarding the secondary endpoint of 1-year mortality, a Cox regression analysis was performed to assess any potential prognostic factors.

All tests were 2-tailed and the differences were considered statistically significant with P values < .05. The statistical analysis was performed using the statistical software package IBM SPSS Statistics V 22.0.

RESULTS

Table 1 shows the baseline characteristics of the patient population. Patients in group 1 were younger (66.5 ± 13.5 years vs 71.1 ± 12.7 years in group 2, and 70.7 13.5) in group 3, P = .016). There were no gender differences among the groups (P = .565). The cardiovascular risk factors, previous coronary artery disease (P = .314), and presence of other comorbidities were similar among the groups (table 1).

Table 1. Baseline characteristics among the 3 study groups and antiplatelet therapy at discharge

	Group 1 (n = 285)	Group 2 (n = 102)	Group 3 (n = 60)	P
Age (years)	66.5 (13.5)	70.7 (13.5)	71.1 (12.7)	.016
Sex (male)	78.9%	80.2%	73.3%	.565
Diabetes	34.9%	37.6%	35.0%	.880
Hypercholesterolemia	63.4%	54.5%	55.9%	.195
Hypertension	71.1%	71.3%	73.3%	.942
GRACE score	157 (44.9)	161 (45.7)	170 (39.6)	.041
CRUSADE score	32.8	34.8	36.4	.251
GFR	72	69.8	66	.118
Peak CK levels	659.9	479.4	590	.623
LVEF at discharge	49.6	54.2	52	.229
Killip class	.604
I	194 (71.3%)	75 (72.7%)	37 (62.7%)
II	32 (11.8%)	15 (15.2%)	9 (15.3%)
III	23 (8.5%)	7 (7.1%)	8 (13.6%)
IV	23 (8.5%)	5 (5.1%)	5 (8.5%)
Mechanical ventilation	29 (10.7%)	6 (6.1%)	5 (8.3%)	.636
Number of vessels with severe stenosis	.488
1	133 (46.8%)	45 (44.6%)	23 (38.6%)
2	77 (27.1%)	23 (22.8%)	22 (36.7%)
3	68 (23.9%)	29 (28.7%)	14 (23.3%)
Successful revascularization	211 (89.8%)	70 (92.1%)	42 (91.3%)	.930
Antiplatelet therapy at discharge
Ticagrelor	154 (54%)	52 (50.9%)	29 (48.3%)	.154
Clopidogrel	105 (36.8%)	40 (39.2%)	24 (40%)	.358
Prasugrel	26 (9.2%)	10 (9.9%)	7 (11.7%)	.469
CK, creatine kinase; GFR, glomerular filtration rate; LVEF, left ventricular ejection fraction. Group 1: coronary angiography within the first 24 h after diagnosis; group 2: 24 h to 72 h later; group 3: coronary angiography > 72 h after diagnosis.

A CA was performed within the first 24 h in 285 patients (63.8%). Surprisingly, we noticed that the patients from group 1 showed lower GRACE scores [157.67 (44.9) points vs 170 (39.5) points in group 3, (P = .041)] and similar CRUSADE scores compared to the other 2 groups (P = .251).

There were no significant differences among the groups in the Killip class at admission (table 1). The left ventricular ejection fraction and the peak values of cardiac biomarkers were similar among the groups. The presence of multivessel disease was similarly in the 3 study groups (table 1). There were no significant differences in the primary endpoint among the 3 study groups (table 2). During hospitalization, strokes and bleeding events occurred similarly in the 3 groups (table 2). It is important to emphasize here the low rate of bleeding events (5 patients with BARC 2 and 2 patients with BARC 3 events in group 1, and 3 patients with BARC 2 and 2 patients with BARC 3 events in groups 2 and 3, with no fatal events). At the 1-year follow-up, cardiovascular adverse events and 1-year mortality were similar among the 3 groups (table 2).

Table 2. In-hospital and follow-up rate of adverse events and mortality (expressed as percentage) among the 3 groups

	Group 1 (n = 285)	Group 2 (n = 102)	Group 3 (n = 60)	P
In-hospital events
Heart failure	74 (25.9%)	26 (25.4%)	21 (36%)	.246
Non-fatal AMI	3 (1%)	4 (3.9%)	3 (6%)	.371
Acute kidney injury	47 (16.5%)	18 (17.6%)	15 (25%)	.334
Stroke	3 (1%)	2 (1.9%)	2 (3.3%)	.548
Bleeding events	20 (7%)	6 (5.8%)	6 (10%)	.213
In-hospital mortality	19 (6.6%)	7 (6.8%)	2 (3.4%)	.358
Events at the 1-year follow-up
Death	17 (5.9%)	5 (4.9%)	5 (8.3%)	.114
Stroke	3 (1.05%)	3 (2.9%)	1 (1.6%)	.271
Major bleeding	7 (2.45%)	6 (5.8%)	4 (6.6%)	.427
Myocardial infarction	16 (5.6%)	5 (4.9%)	4 (6.6%)	.907
AMI, acute myocardial infarction. Group 1: coronary angiography within the first 24 h after diagnosis; group 2: 24 h to 72 h later; group 3: coronary angiography > 72 h after diagnosis.

Regarding medical treatment at discharge, a similar percentage of patients received clopidogrel, prasugrel and ticagrelor in the 3 study groups (table 1). In our cohort, antiplatelet therapy was not associated with differences in the rate of major adverse cardiovascular events and mortality at the 12-month follow-up.

The multivariate logistic regression analysis performed to predict mortality revealed that hypertension, Killip class IV at admission, left ventricular ejection fraction, and myocardial damage (defined as peak creatine kinase levels) were independently associated with higher in-hospital mortality rates. The time to CA was not an independent predictor of in-hospital mortality after the multivariate adjustment (table 3).

Table 3. Multivariate logistic regression analysis to predict in-hospital mortality

Variable	Odds ratio (95%CI)	P
CA after 72 h	reference
CA within the first 24 h	0.98 (0.26-3.74)	.978
CA 24 h to 72 h later	1.33 (0.28-6.24)	.716
Hypertension	6.25 (1.09-33.3)	.04
Age (per year)	1.03 (0.98-1.08)	.292
Successful revascularization	0.51 (0.12-2.21)	.371
Peak CK levels (per pg/mL)	1.00 (1.00-1.01)	.010
LVEF	0.93 (0.90-0.97)	< .001
Killip class at admission
I	reference	.026
II	3.39 (0.98-11.75)	.054
III	3.24 (0.92-11.36)	.067
IV	15.34 (2.19-107.58)	.006
95%CI, 95% confidence interval; CA, coronary angiography; CK, creatine kinase; LVEF, left ventricular ejection fraction.

Regarding 1-year mortality, the Cox regression analysis showed similar results. The time to CA was non-significant in the multivariate analysis. Hypertension, age, left ventricular ejection fraction, and Killip class at admission were independently associated with higher mortality rates at 1 year (table 4).

Table 4. Multivariate Cox regression analysis to predict 1-year mortality

Variable	Hazard ratio (95%CI)	P
CA after 72 h	reference
CA within the first 24 h	0.96 (0.46-2.03)	.919
CA 24 h to 72 h later	0.82 (0.33-2.07)	.677
Hypertension	3.64 (1.30-10.3)	.014
Age (per year)	1.04 (1.01-1.07)	.022
Successful revascularization	0.94 (0.41-2.13)	.876
Peak CK levels (per pg/mL)	1.00 (1.00-1.01)	.198
LVEF	0.96 (0.94-0.98)	< .001
Killip class at admission
I	reference
II	2.83 (1.32-6.08)	.008
III	2.78 (1.27-6.09)	.010
IV	2.91 (0.83-10.2)	.096
95%CI, 95% confidence interval; CA, coronary angiography; CK, creatine kinase; LVEF, left ventricular ejection fraction.

DISCUSSION

Our study included a large cohort of 447 consecutive patients with NSTEMI that were retrospectively analyzed. Our results showed that early CAs (defined as a CA performed within the first 24 h after diagnosis) in NSTEMI patients did not improve the prognosis of this cohort of patients compared to delayed CAs. No differences were seen among the 3 groups regarding the time to CA in the in-hospital cardiovascular adverse event rate, mortality rate or at the 12-month follow-up either.

Early CA, within the first 24 h after diagnosis, is currently recommended by the clinical practice guidelines for the management of patients with NSTEMI. However, this recommendation is based on the results of relatively old clinical trials and a meta-analysis.4^-8 Several recent trials have explored the prognostic impact of the CA timing on NSTEMI patients in order to find stronger evidence in this clinical setting.9^,10

The results of the TIMACS study (Timing of Intervention in Acute Coronary Syndromes) showed that an early CA was associated with a reduction in the composite endpoint of death, myocardial infarction or refractory ischemia compared to a delayed CA strategy.11

A retrospective cohort study that included 19 704 propensity scorematched patients hospitalized with a first acute coronary syndrome conducted between January 1, 2005 and December 31, 2011 showed that the use of an early invasive treatment strategy was associated with a lower risk for cardiovascular mortality and re-hospitalization due to myocardial infarction compared to a conservative invasive approach.12 However, it is important to emphasize the retrospective nature of this study and the fact that patients were followed for 60 days only.

However, a meta-analysis that combined data from 83 229 patients did not show any significant differences regarding mortality, myocardial infarction or major bleeding events between the 2 strategies.13

Another meta-analysis that included 8 randomized controlled trials (n = 5324 patients) with a median follow-up of 180 days [180-360] and compared an early invasive group of NSTEMI patients to a delayed strategy showed that the early invasive strategy did not reduce mortality in all NSTEMI patients including high risk patients with GRACE score > 140 points.14

Similarly, a recent meta-analysis that combined the results of 10 clinical trials did not find any differences in mortality, myocardial infarction or major bleedings among NSTEMI patients based on the CA timing. Nevertheless, the early CA strategy was associated with less recurrent angina and shorter hospital stays.15

The LIPSIA-NSTEMI study randomized patients with NSTEMI to undergo CA within the first 2 h after randomization (immediate CA strategy), 10 h to 48 h after randomization (early CA), and the so-called “selectively invasive” arm, in which patients initially received medical treatment without showing any differences in the infarct size among the 3 study groups.16

A recent randomized controlled trial conducted by a Kofoed et al., the VERDICT trial, included a total of 2147 patients of which 1075 were allocated to very early invasive evaluation (within the first 12 h after diagnosis), and 1072 to receive standard invasive care (CA 61.6 h after randomization).17 The primary endpoint was a composite of all-cause mortality, nonfatal recurrent myocardial infarction, refractory myocardial ischemia-related hospital admission or heart failure-related hospital admission. In this trial, the very early invasive coronary evaluation strategy did not improve overall the long-term clinical outcome compared to the invasive strategy performed within 2 to 3 days in patients with non-ST-segment elevation acute coronary syndrome. However, in patients with the highest risk, the very early invasive therapy improved long-term outcomes17 which is consistent with the results shown by the TIMACS trial.

Despite all these data, there is still controversy on what the best timing is to perform a CA in patients with NSTEMI.

An important limitation of previous studies is heterogeneity in the definition of early and late CA, and the differences seen in the primary endpoints.4^-14 The lack of uniform criteria makes it difficult to compare the results. The definition of NSTEMI has changed over time. Thus, old clinical trials used a different criterion for the definition of NSTEMI and included different patients from those of current studies. We should try to identify what patients with the highest risk would benefit from an early invasive strategy. In this sense, previous studies did not use risk grading systems to classify patients. However, in our study we calculated the ischemic and bleeding risks of all patients. As our objective was to assess the potential benefit of an early invasive strategy among NSTEMI patients, the GRACE risk score was estimated in the entire study population. However, despite the high ischemic risk of our patients, no significant differences were found between the 2 strategies (early or delayed CA) regarding mortality or adverse events.

Limitations

Our study has several limitations that should be considered when interpreting the results. Although we included a large number of NSTEMI patients with a collection of high quality data, this is an observational, retrospective, single center study with the limitations of this type of study. Besides, the current clinical practice guidelines recommend the PRECISE-DAPT score to assess bleeding risk in this clinical setting. In our study bleeding risk at admission was classified according to CRUSADE score.

CONCLUSIONS

The results of our study show that the early CA strategy did not improve prognosis or reduce mortality in NSTEMI patients. However, larger studies are still needed to clarify which group of patients may benefit from early CA strategies.

CONFLICTS OF INTEREST

None declared.

 

 

REFERENCES

INTRODUCTION

The prevalence of chronic total coronary occlusions (CTO) is around 16% to 52% in patients with significant coronary artery disease on the angiography.1 In the presence of a CTO, collateral blood supply is often enought to maintain resting perfusion and contractility in the collateral-dependent myocardium.2 Restoration of antegrade flow by the percutaneous coronary intervention (PCI) of a CTO is associated with a rapid reduction in the collateral supply received in the treated vessel.3

Randomized trials support the use of fractional flow reserve (FFR) to guide the PCI with an established treatment threshold of ≤ 0.8.4^-8 Although the FFR is reported to be independent of hemodynamic changes,9 it is intimately related to total coronary flow through a stenosis, which in turn is related to perfused myocardial mass.10 In keeping with this, there have been several reports of normalization of FFR values from collateral donor vessel after successful recanalization of a CTO.11 By removing nutrient flow to the collateralized territory by CTO recanalization, the collateral network almost immediately increased its resistance, thus favoring flow to the donor territory during maximal hyperemia.12

In patients with Rentrop grade-2 or grade-3 collateral flow, the FFR value of the donor artery increased at least 0.10 after revascularization of the recipient artery. However, the FFR value did not change significantly in patients with Rentrop grade-0 or grade-1 collateral flow following revascularization. This suggests that well-developed collateral circulation might overestimate the FFR value in the donor artery with mild stenosis.13

The assessment of myocardial-perfusion through cardiovascular magnetic resonance imaging (CMR) is a noninvasive imaging modality for the detection of coronary artery disease with a high degree of concordance with the FFR for ischemia detection.14^-16 Also, the CMR has emerged as robust and reproducible method to assess the ischemia and viability of the myocardium related to the CTO.17^-19 The MR-INFORM trial showed that in patients with stable angina and risk factors for coronary artery disease, the CMR of myocardial perfusion was associated with a lower incidence of coronary revascularization compared to the FFR and was noninferior to the FFR regarding major adverse cardiovascular events (all-cause mortality, non-fatal myocardial infarction or target-vessel revascularization) at 12 months.20 However, it is uncertain whether opening a CTO can modify the amount of ischemia related to an angiographically intermediate lesion of the collateral donor vessel. It could also be possible to diagnose microvascular dysfunction using CMR.21

Therefore, in this pilot study, using the FFR we assessed changes in the amount of ischemia related to the angiographically intermediate stenosis of collateral donor vessel before and immediately after the successful PCI of a CTO. We also tried to determine any changes in the amount of ischemia using the CMR prior to the PCI and 1 month after recanalization.

METHODS

In this prospective pilot study, we included patients with stable angina and CTO with collateralization of the distal vascular bed, and collateral donor vessel with a single angiographically intermediate lesion (50%-70% diameter stenosis by quantitative coronary angiography). In order to indicate recanalization through PCI all patients were referred for CMR evaluation to assess the presence of myocardial viability. During the procedure, the FFR of the donor vessel was measured before the PCI of the CTO (figure 1). Only with FFR values ≤ 0.80, the measure was reassessed after the procedure (figure 2). A second CMR was performed 1 month after the index PCI. All patients gave their informed consent, the local ethics committee approved the study, and all procedures were performed in accordance with the Helsinki Declaration. The study population was clinically followed for 2 years. The rate of major adverse cardiovascular events was established. This was defined as a composite of all-cause mortality, non-fatal acute myocardial infarction (AMI), clinically-driven target vessel revascularization or rehospitalization due to unstable or progressive angina according to Braunwald Unstable Angina Classification. The exclusion criteria were: prior IAM; failed recanalization of the CTO, inability to obtain signed written informed consents; severity of valvular heart disease; acutely decompensated chronic heart failure; asthma or obstructive sleep apnea; high risk of bleeding; known hypersensitivity or contraindication to aspirin; nursing subjects; patients with pacemakers/implantable cardioverter- defibrillators.

Figure 1. Example of chronic total coronary occlusion (CTO) of right coronary artery (panel A, yellow arrows) with collateralization of distal vascular bed, and left main and left anterior descendent artery (LAD) as the collateral donor vessel shows an angiographically intermediate lesion (panel B, yellow circles). During the procedure, the fractional flow reserve (FFR) of the donor vessel was measured before the percutaneous coronary intervention of the CTO (panel C).

Figure 2. Example of the recanalization of chronic total coronary occlusion (CTO) of the right coronary artery (panel A) with left anterior descendent artery (LAD) as the collateral donor vessel shows an angiographically intermediate lesion (panel B, yellow circles). Panel C: after the CTO repermeabilization, the fractional flow reserve (FFR) value of the LAD increased (FFR value = 0.91).

The percutaneous coronary intervention

The PCI was performed using bilateral femoral artery access and 7-Fr sheaths and guide catheters. Anticoagulation was achieved with 100 U/Kg of unfractionated heparin to maintain activated clotting times of 250-300 msec. All the procedures on the CTO were performed using the antegrade wire escalation technique. All patients were treated with drug-eluting stent implantation. The J-CTO score was calculated for each CTO lesion and assessed taking the following parameters into consideration: occlusion length, stump morphology, presence of calcification, presence of tortuosity and prior attempt to open the CTO.22 Collateral flow was graded in accordance with Rentrop collateral flow classification.23 Procedural success was defined as achievement of residual post-PCI stenosis < 30% in the target lesion associated with TIMI grade-3 flow without mortality, IAM or new lesion revascularization during the index hospitalization.

Assessment using fractional flow reserve

To measure FFR in the intermediate coronary lesions a 0.014-inch pressure-monitoring guidewire (Prime Wire Volcano Therapeutics, Inc, Rancho Cordova, CA, United States) was used. After calibration of both the aortic and wire pressures, the FFR wire was advanced until the tip of the guiding catheter. Equalization of both pressures was performed. Then, the wire was advanced and positioned distally at least 15 mm from the stenotic lesion followed by the administration of 0.2 mg of nitroglycerin to avoid any form of epicardial vasoconstriction. Maximal hyperemia was induced through the IV infusion of adenosine (180 µg/kg/min). After reaching the steady state we measured the FFR as the ratio between mean distal coronary pressure and mean aortic pressure. Values < 0.80 were considered significant from the hemodynamical standpoint. After FFR measurement and under maximal hyperemia, the pressure wire was pulled back until the sensor was close to the tip of the guiding catheter to make sure that no drift had occurred.

Cardiovascular magnetic resonance imaging

All CMR studies were performed using a General Electric Signa HDxt 1.5-T scanner equipped with an 8-channel coil and cardiac-dedicated software. Perfusion studies were conducted using a gradient-echo turbo-field sequence prescribed in the left ventricular short-axis orientation, at the basal, mid-ventricular and apical levels after 4 min of IV administration of adenosine (Atepo-din) at a dose of 180 µg/kg/min and simultaneous administration of 0.1 mmol/kg of gadobutrol (Gadovist, Bayer Hispania) at a 5 mL/s rate. The functional and volumetric assessment of the left ventricle (LV) was conducted using the conventional Steady State Free Precession (SSFP) cine sequence, prescribed in sequential short-axis slices, and encompassing the entire LV and the 2-, 3-, and 4-chamber views. The typical temporal and in-plane spatial resolution of these images was 40 ms and 1.4 × 1.4 mm, respectively. Rest perfusion images were obtained at least 10 min after the stress perfusion study using the same sequence, location, and contrast injection protocol. Ten minutes after administering the dose of gadolinium for the rest perfusion study, late gadolinium-enhanced images were obtained using a segmented inversion-recovery spoiled gradient echo sequence in the same location and identical spatial resolution as the cine images. To calculate left ventricular ejection fraction (LVEF), the LV mass and left ventricular end-systolic and end-diastolic volumes, the endocardial and epicardial borders were manually traced at end-systole and end-diastole in the cine short-axis images using a dedicated software package (ReportCard, GE). The regional wall motion analysis was performed by visual grading of the cine images according to the 17-segment model proposed by the American Heart Association.17 The pre- and post-PCI image analysis was conducted by 2 independent experienced operators masked to the patient’s coronary anatomy and the PCI results; the disparities in their evaluation were resolved by consensus with a third independent operator. The appropriate allocation between the involved myocardial segments and the correspondent coronary anatomy in each case was evaluated according to previously reported criteria.18

Statistical analysis

The distribution of continuous variables was assessed by visual inspection of frequency histograms and using the Shapiro–Wilk test. Continuous variables were expressed as mean ± standard deviation (SD) or median with interquartile range (IQR) when they followed a normal or non-normal distribution, respectively. The continuous variables were compared using the unpaired Student t test or Mann–Whitney U test and the categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate. Correlations between variables were conducted using the Pearson test. The software SPSS 17.0 (SPSS Italy, Florence, Italy) was used for statistical analyses.

RESULTS

We screened 23 patients with stable angina and CTO with collateralization of distal vascular bed, and collateral donor vessel with angiographically intermediate lesion. We excluded 9 patients who showed some exclusion criteria. Fourteen patients were finally included in the study (figure 3). The clinical characteristics and angiographic details are shown on table 1. Seven intermediate lesions (50%) of the collateral donor vessels showed FFR values ≤ 0.80 before the recanalization of the CTO. On average, FFR measures significantly increased after CTO revascularization (0.75 [0.73-0.78] vs 0.83 [0.81-0.84]; P = .017) (table 2 and figure 4). Four patients normalized their FFR values, while in the other 3 the FFR remained hemodynamically significant and required subsequent PCI. There was a tendency towards a reduction of the number of ischemic segments assessed through CMR before and after the recanalization of the CTO (2.5 [0-4] vs 0 [0-0.25]; P = .066). No differences were found in other parameters including the number of hypokinetic segments, left ventricular ejection fraction, left ventricular end-diastolic and end-systolic volumes; left ventricular mass; and necrotic mass before and after the PCI (table 2). In addition, the number of ischemic segments did not significantly correlate with the FFR values before or after PCI (R² = -0.31, P = .328; R² = -0.68, P = .20, respectively). Finally, no major adverse cardiovascular events were reported during the 2-year follow-up.

Figure 3. We screened 23 patients with stable angina and chronic total occlusion (CTO) with collateralization of distal vascular bed, and collateral donor vessel with angiographically intermediate lesion; 9 of them were excluded after meeting the exclusion criteria. In particular, 3 contraindications for dual antiplatelet therapy, 1 valvular heart disease requiring surgery, 3 refusals to sign the informed consent, and 3 pacemakers. CMR, cardio­vascular magnetic resonance; PCI, percutaneous coronary intervention.

Table 1. Clinical and angiographic characteristics

Clinical characteristics	Patients (n = 14)
Age, years	67.44 ± 12.9
Male	12 (85)
Hypertension	6 (42.8)
Smoking	2 (14.3)
Hyperlipidemia	10 (71.4)
Diabetes Mellitus	5 (35.7)
Renal failure	2 (14.3)
Prior CABG	1 (7.1)
Medical treatment
Beta-blockers	5 (35.7)
Calcium antagonist	2 (14.3)
ACE inhibitor	4 (28.5)
Statins	10 (71.4)
Angiographic characteristics
CTO vessel
LAD	2 (14.3)
LCX	1 (7.1)
RCA	11 (78.6)
Calcification	7 (50%)
Bending > 45 degrees	2 (14.3)
Tapered	8 (57.1)
Occlusion length, mm	24.6 [6-43.3]
Rentrop > 1	13 (92.8)
J-CTO score > 2	3 (21.4)
Collateral donor vessel
LAD	7 (50)
LCX	4 (28.6)
RCA	3 (21.4)
Stenosis degree	52 [50-55]
Data are expressed as n (%), mean ± standard deviation or median [interquartile range]. ACE, angiotensin converting enzyme; CABG, coronary artery bypass grafting; CTO, chronic total occlusion; IQR, interquartile range; JCTO, Japanese CTO; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery.

Figure 4. Fractional flow reserve (FFR) values of 7 angiographically intermediate lesions in the collateral donor vessels before and after the percutaneous coronary intervention (PCI) of a chronic total coronary occlusion.

Table 2. FFR and CMR measures in the study population

	Before PCI (n = 7)	After PCI (n = 7)	P
Pd/Pa	0.93 (0.88-0.96)	0.91 (0.89-0.93)	1.00
FFR	0.75 (0.73-0.78)	0.83 (0.81-0.84)	.017
IS	2.5 (0.0-4.0)	0.0 (0.0-0.25)	.066
HS	1.0 (0.0-4.75)	0.0 (0.0-0.50)	.15
LVEF, %	60.5 (55.0-63.25)	63.5 (54.0-65.25)	.41
LVEDV, ml	111.3 (102.7-451.1)	109.0 (100.6-139.2)	.50
LVESV, ml	41.1 (38.6-65.17)	38.9 (35.2-81.4)	.49
LV mass, gr	83.4 (56.4-92.1)	88.5 (69.1-110.2)	.50
NM, gr	0.83 (0.3-2.3)	0.92 (0.4-1.5)	1.0
CMR, cardiovascular magnetic resonance imaging; FFR, fractional flow reserve; HS, hypokinetic segments; IS, ischemic segments; LV, left ventricular; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; NM, necrotic mass; Pd/Pa: resting distal coronary pressure to aortic pressure ratio; PCI, percutaneous coronary intervention. Data expressed as median (interquartile range).

DISCUSSION

These are the main findings of the study: a) functional assessment of intermediate lesions located in the collateral donor artery showed significantly lower FFR values than it would have in the absence of collateralized CTOs; b) after the recanalization of the CTO, the FFR values of the collateral donor artery normalized in most of patients; c) the amount of ischemia assessed through CMR used to decrease after successful CTO recanalization; d) no major adverse cardiovascular events were reported in our population at the long-term follow-up.

The FFR is a method used to assess the functional significance of coronary stenosis while taking in account the following parameters: severity of stenosis, myocardial territory and viability, and collateral perfusion.19 Results from the FAME trial showed that FFR-guided PCI was superior to the angiography-guided PCI at 1 and 2 years in terms of death or AMI and AMI alone.5^,11 In the FAME 2 trial, the FFR-guided PCI reduced the rate of major adverse cardiovascular events compared to medical therapy alone.6 To this day, physiology has been proposed to outline which stenoses should be treated in the context of multivessel disease.24 However, there is uncertainty around what the waiting time is before performing an accurate pressure wire assessment of donor arteries after the successful recanalization of a CTO. Several studies have shown that full collateral regression does not happen immediately after the successful revascularization of a CTO.3 During embryonic development, collaterals derive either from capillary sprouting or pre-existing arteriolar connections.25 Collateral growth occurs through 2 major processes: arteriogenesis and angiogenesis. The former, stimulated by physical forces, consists of the growth, positive remodeling, and expansion of preexisting collateral vessels. The latter, induced by hypoxia, is the de novo growth of new capillaries by sprouting or intussusception from pre-existing vessels.26 Although once established, coronary collaterals are believed to persist and can be re-recruited, this process does not happen immediately. Well-developed collateral vessels close when the pressure gradient across the collateral network disappears. Also, the time needed to reopen the closed collaterals after reestablishing the pressure gradient seems to be directly related to the time interval between coronary occlusions.27 Recently, Mohdnazri et al. have showed that the successful recanalization of a right coronary artery CTO resulted in a modest but statistically significant and immediate increase of instantaneous wave-free ratio (iFR) in the predominant donor vessel following the recanalization of the CTO. At 4 months, both the FFR and the iFR showed significant improvement compared to pre-PCI values together with a concomitant reduction of collateral function.28 Ladwiniec et al. showed that the recanalization of a CTO resulted in a modest FFR increase of the predominant collateral donor vessel associated with a reduced coronary flow, of a similar magnitude at baseline and maximal hyperemia.29 Few patients of our study did not show this improvement. The persistence of non-angiographically visible collateral circulation, the presence of microcirculation dysfunction and type of prior collateral circulation grade,30 and distal embolization or myonecrosis following PCI recanalization may be potential causes of this lack of improvement. In this regard, in a recent study, measurements repeated shortly after the PCI of a CTO showed transient procedural-related changes like microvascular dysfunction secondary to distal embolization, catecholamine release, left ventricular stunning or hyperemic stimulus related to side-branch occlusion.29

Our data suggest that in the setting of CTOs and an angiographically intermediate lesion of the collateral donor vessel, it seems like the FFR measurement may be misleading. Therefore, it seems advisable to postpone the assessment of intermediate stenoses until achieving the successful recanalization of the associated CTO. This approach should avoid overtreating patients who only require the revascularization of their CTOs. On the contrary, if the recanalization of the CTO fails, treating the intermediate stenosis in the donor artery may be necesary to reduce ischemia in this territory. It also still is a good practice to try to re-open the CTO prior to performing any interventions on the donor vessel, due to the risk of extensive acute ischemia in case of troublesome PCIs.

Moreover, we did not find any correlations between the amount of ischemia assessed through CMR and the FFR values before or after the PCI. As far as we know, this is the first comparison between CMR and FFR assessment of an angiographically intermediate lesion in a collateral donor vessel related a CTO. Former studies have suggested that the CMR underestimates or that the FFR overestimates the number of ischemic segments in multi-vessel disease.31^-32 This discrepancy seems to highlight the poor accuracy of the FFR method in the presence of collaterals involving territories that are from the target lesion to be assessed.

Finally, after treating the patients according to the FFR measures obtained after the PCI of a CTO, no major adverse cardiovascular events were detected at the 2-year follow-up.

Limitations

Several limitations should be acknowledged. First, due to the small size of the sample our findings should be, at best, hypothesis- generating findings. Secondly, we only used FFR as hyperemic index; other indices (eg. iFR, IMR, etc.) were not assessed. Similarly, we could not assess the influence of microcirculation through CMR or hyperemic microvascular resistance. Third, we did not assess whether collateral circulation originated from a segment proximal or distal to the target stenosis under study. Fourth, in patients with negative FFR before the recanalization of their CTO we did not repeat the FFR after the PCI. Finally, no follow-up CMRs were performed in patients with negative FFR prior to recanalization.

CONCLUSIONS

The FFR assessment of intermediate stenoses in a collateral donor vessel of a CTO may overestimate the severity of the lesion by increasing the territory at risk. Therefore, the strategy of first focusing on the revascularization of the CTO and then re-assess the intermediate lesion in a collateral donor vessel may be recommended to overcome this pitfall.

CONFLICTS OF INTEREST

The authors have no conflicts of interest to declare.

 

 

REFERENCES

INTRODUCTION

Primary percutaneous coronary intervention (pPCI) is the preferred treatment for the management of ST-segment elevation myocardial infarction.1 However, one of its limitations is the possibility of distal embolization of thrombus and failure to restore flow at the microvascular level, which is associated with a significantly higher mortality rate.2 Thrombus aspiration (TA) was thought to be a simple method to remove thrombus before stent deployment, thereby reducing distal embolization and improving outcomes.3

After the promising results of the TAPAS trial,4^,5 TA was included in the routine practice and was probably overused.6 However, the results from the TASTE8 and TOTAL9 clinical trials have brought uncertainty to the clinical benefits of TA. Additionally, possible harm from an increased risk of stroke has been suggested.9 Subsequently, guidelines have downgraded the indication for routine TA from IIa10^-12 to III,13^,14 resulting in a progressive reduction in the use of TA (figure 1).4^,7^,9^,15

Figure 1. Evolution of pPCI and TA over the last 15 years: Evolution of primary percutaneous coronary intervention and TA in Spain over the last 15 years15 in relation to the publication of the main TA trials.4^,7^,9 pPCI, primary percutaneous coronary intervention; TA, thrombus aspiration.

In addition to the fact that the above-mentioned clinical trials may not reflect the actual clinical practice,6 we should be consider that these recommendations apply for routine TA and not for selective TA, where the operator performs the technique in cases where the expected benefit is higher. Although selective TA may be more indicative of the common practice, we do not have actual data on its application. For this reason, we designed the TAPER registry (efficacy and safety of selective Thrombus Aspiration in Real clinical Practice) in an attempt to analyze the procedural advantages of selective TA during pPCI, its safety and clinical benefit at 1-year of follow-up.

METHODS

Patients and study design

The TAPER registry retrospectively included patients with ST-segment elevation myocardial infarction treated with pPCI in 4 high-volume centres of different countries (A, B, C, D) on a 24/7 program. These centers serve communities of 615 000, 400 000, 450 000, and 350 000 people, respectively.

Consecutive patients with ST-segment elevation myocardial infarction who were referred to undergo pPCI within 12 hours after symptoms onset in the period between January 2015 and December 2016 were included. Those who had received fibrinolytic therapy were not eligible.

We excluded those patients who did not have an evident culprit coronary lesion, those who presented with cardiac arrest and those who were lost to follow-up. Patients with contraindications to antiplatelet therapy were also excluded (figure 2).

Figure 2. Study flowchart. P, patients; pPCI, primary percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; TA, thrombus aspiration.

The TA group was defined as those patients in whom the TA was performed as an initial strategy and non-TA group as those patients in whom the TA was not performed or it was performed as a bailout strategy after balloon dilatation or stent implantation.

Both the clinical and procedural characteristics were analyzed and a combined endpoint of cardiovascular mortality, non-fatal myocardial infarction related to the treated lesion, stent thrombosis, target lesion revascularization or stroke was evaluated at 1-year follow-up.

Study procedures

Patients received antiplatelet and anticoagulant treatment according to the clinical practice guidelines.16 The addition of IIb/IIIa glycoprotein inhibitors was left to the discretion of the operator. The use of TA and other technical details of the pPCI were left at the discretion of the interventional cardiologist. TA was performed using a standard technique.9

Angiographic assessment

The angiographic analysis was performed by 4 experienced interventional cardiologists. After defining the culprit lesion in the initial coronary angiogram, the distal flow of the culprit vessel was assessed using the Thrombolysis in Myocardial Infarction (TIMI) grade score.17 Once the culprit lesion had been crossed with a coronary guidewire, the thrombotic burden was defined according to the TIMI-thrombus scale.18 Both the TIMI-flow scale and the TIMI-thrombus scale were reassessed after the TA. The presence of no-reflow phenomenon and thrombus distal embolization were also evaluated.

Follow-up and clinical endpoints definitions

The follow-up of the patients was carried out through telephone calls and in-hospital clinical records of the visits to the cardiology department after the initial admission.

The occurrence of major acute cardiovascular events (MACE) [cardiovascular mortality, myocardial infarction related to the treated lesion, stent thrombosis or need for revascularization of the treated lesion or stroke] at 1-year follow-up was established as the primary endpoint. The secondary endpoints were the independent analysis of each individual event of the composite endpoint.

All deaths were considered cardiac unless another specific cause was documented. Myocardial infarction was defined following the actual recommendations19 and only those related to the treated lesion, whether periprocedural or at follow-up, were taken into consideration. Target lesion revascularization or stent thrombosis was defined according to the Academic Research Consortium criteria.20

The angiographic success was defined as final TIMI 3 distal flow with less than 20% of vessel stenosis and no immediate mechanical complications. TA was considered successful if an improvement of TIMI-flow ≥ 1 grades or a reduction of TIMI-thrombus scale ≥ 1 grades were achieved, without any immediate complications related to the technique.

Statistical analysis

Quantitative variables following a normal distribution were expressed as mean ± standard deviation. Those that did not follow were described by the median [range]. Qualitative variables were expressed as absolute and relative frequencies of their categories.

P levels < .05 were considered statistically significant and the 95% confidence interval (95%CI) of the target analysis variables was estimated. When it comes to the bivariate analysis, the Student t test or the non-parametric Mann-Whitney U test were used for mean comparison purposes and the chi-square test or Fisher’s exact test were used to compare qualitative variables.

For the multivariate analysis, logistic regression was used. Variables were considered as potential predictors of risk in the multivariate model when they showed a statistically significant association in the univariate analysis. The SPSS statistical package software version 20 (Armonk, NY: IBM Corp), was used for calculations.

RESULTS

Out of the 761 patients initially screened, 74 were excluded (18 patients did not have any evident culprit coronary lesions, 48 patients presented with cardiac arrest, and 8 patients were lost to follow-up). The remaining 687 patients (64.1 ± 12.2 years; 76.9% male) were finally analyzed. The baseline characteristics are shown on table 1.

Table 1. Baseline characteristics

	TA group N = 250	Non-TA group N = 437	P
Age (y)	63.6 ± 12.6	64.4 ± 12.1	.46
Male	208 (83.2%)	320 (73.2%)	.003
BMI	27.2 ± 6.4	26.6 ± 5.8	.23
Current smoker	105 (42%)	140 (32%)	.012
Diabetes mellitus	44 (17.6%)	80 (18.3%)	.86
Dyslipidemia	74 (29.6%)	103 (23.6%)	.07
Hypertension	114 (45.6%)	195 (44.6%)	.68
LVEF	48.7 ± 10.7	49.7 ± 10.4	.27
Previous PCI	27 (10.8%)	37 (8.5%)	.29
Previous CABG	3 (1.2%)	5 (1.1%)	.93
Chronic kidney disease	13 (5.2%)	13 (2.9%)	.14
BMI, body mass index; CABG, coronary artery bypass grafting; LVEF, left ventricle ejection fraction; PCI, percutaneous coronary intervention; TA, thrombus aspiration. Data are expressed as no. (%) or mean ± standard deviation.

Procedural characteristics

In the overall cohort, the culprit lesion was more frequently located at the left anterior descending coronary artery (45.6%), followed by the right coronary artery (36.9%). Forty-eitgh-point-one per cent of patients had multivessel disease. The initial TIMI-flow was 0-1 in 72.7% of cases and the TIMI-thrombus grade was ≥ 3 in 61.6% of the cases.

The TA was performed in 40.3% of cases. In 89.9%, the TA was the initial strategy after crossing the culprit lesion with the coronary guidewire, whereas in 10.1% of the cases it was performed as a bailout strategy (figure 3). Procedural characteristics are shown on table 2.

Table 2. Angiographic and procedural characteristics

	TA group n = 250	Non-TA group n = 437	P
Culprit artery			.01
LM	5 (2%)	2 (0.5%)
LAD	98 (39.2%)	209 (47.8%)
LCx	30 (12%)	71 (16.2%)
RCA	114 (45.6%)	148 (33.8%)
Other	3 (1.2%)	1 (0.2%)
Multivessel disease	107 (42.8%)	221 (50.6%)	.08
P2Y12 inhibitor			< .0001
Clopidogrel	185 (74%)	272 (62.2%)
Prasugrel	15 (6%)	29 (6.6%)
Ticagrelor	37 (14.8%)	119 (27.2%)
Anticoagulation			.69
UFH	245 (96%)	433 (99%)
Bivalirudin	2 (0.8%)	2 (0.45%)
Enoxaparin	0 (0%)	1 (0.22%)
Glycoprotein IIb/IIIa inhibitor			.13
Abciximab	91 (36.4%)	120 (27.5%)
Eptifibatide	15 (6%)	18 (4.1%)
Ventricular assist device	11 (4.4%)	12 (2.7%)	.24
Initial TIMI-flow	0.3 ± 0.8	1.1 ± 1.3	< .0001
Initial TIMI-flow 0-1	228 (91.2%)	271 (62%)	< .0001
Initial TIMI-thrombus grade	4.8 ± 0.9	2.5 ± 1.4	< .0001
Initial TIMI-thrombus grade ≥ 3	233 (93.2%)	191 (43.7%)	< .0001
Initial stent thrombosis (as culprit lesion)	14 (5.6%)	7 (1.6%)	.004
Bifurcation (at the culprit lesion)	62 (24.8%)	108 (24.7%)	.8
DTB time (minutes)	101 ± 55	102 ± 83	.8
TA device
Medtronic Export	134 (53.6%)	NA
Terumo Eliminate	96 (38.4%)	NA
Hexacath Recover	20 (8%)	NA
Direct stenting	178 (71.2%)	144 (32.9%)	< .0001
Type of stent			.04
Bare metal	80 (32%)	108 (24.7%)
Drug-eluting	170 (68%)	329 (75.3%)
Stent length (mm)	29 ± 13.8	27.8 ± 14.8	.29
Stent diameter (mm)	3.3 ± 0.7	3.4 ± 2.2	.8
Post-dilatation	43 (17.2%)	82 (18.8%)	.47
No reflow	24 (9.6%)	31 (7.1%)	.24
Distal embolization	4 (1.6%)	7 (1.6%)	.97
Angiographic success	238 (95.2%)	404 (92.4%)	.16
DTB, door-to-balloon time; LAD, left anterior descending coronary artery; LCx, left circumflex artery; LM, left main coronary artery; RCA, right coronary artery; TA, thrombus aspiration; TIMI, Thrombolysis in Myocardial Infarction. Data are expressed as no. (%) or mean ± standard deviation.

Figure 3. Selective TA performance and beneficial effects during primary percutaneous coronary intervention. Percentage of cases in which TA was used (as an initial or bailout strategy) and TA success rate by improving TIMI-flow or TIMI-thrombus grade. TA, thrombus aspiration; TIMI, Thrombolysis in Myocardial Infarction.

Predictors of use of thrombus aspiration

There were significant differences in the use of TA rates among the different centers (A = 63.7%; B = 32.9%; C = 16.9%; D = 15.7%; P < .0001). The TA was more frequently used as the initial strategy in male patients (40.9% vs 26.4%; P = .003), in current smokers (47.7% vs 36.1%; P = .012), and when the culprit lesion was the thrombosis of a former stent (66.7% vs 36%; P = .004). The rate of TA was also different when it comes to the culprit artery (left anterior descending coronary artery, 31.9%; left circumflex coronary artery, 29.7%; right coronary artery, 43.5%; P = .01). Also, the patients from the non-TA group were treated more often with ticagrelor or prasugrel compared to clopidogrel (P < .0001) and received more frequently drug-eluting stents (TA group, 68% vs non-TA group, 75.3%; P = .04). In the patients from the TA-group, the initial TIMI-flow was significantly lower (0.3 ± 0.8 vs 1.1 ± 1.3; P < .0001) and the initial TIMI-thrombus grade was higher (4.3 ± 0.9 vs 2.5 ± 1.4; P < .0001).

In the multivariate analysis, we included those variables that showed a statistically significant association with TA in the univariate analysis: gender, current smoking habit, culprit artery, P2Y₁₂ inhibitor, initial TIMI-flow, initial TIMI-thrombus grade, initial stent thrombosis (as culprit lesion), center and type of stent. The strongest independent predictor for the use of TA as the initial strategy was a higher initial TIMI-thrombus grade (odds ratio [OR], 3.2; 95%CI, 2.5-3.9; P < .0001). The performance of the pPCI in center A (OR, 20.7; 95%CI, 10-42.5; P < .0001) or B (OR, 3.3; 95%CI, 1.4-7.5; P = .005) was also an independent predictor of TA (compared to center D; the center where the TA was less frequently used). Culprit lesions located at the right coronary artery [OR, 2; 95%CI, 1.008-3.9; P = .047] were also identified as predictors for the use of TA as the initial strategy.

Angiographic results after thrombus aspiration

When TA was performed as initial strategy, a significant improvement of TIMI-flow (2.4; 95%CI, 2.2-2.5; P < .0001) and a significant reduction of TIMI-thrombus grade [2.6; 95%CI, 2.4-2.8; P < .0001] were observed (figure 3). There were no significant differences between both groups in the occurrence of no-reflow phenomenon or distal embolization. The rate of direct stenting was twice as frequent in the TA group. Similarly, the rate of procedural success was high and similar in both groups (TA group, 95.2% vs non-TA group, 92.4%; P = .16) (table 2).

Adverse events at follow-up

After a 1-year follow-up, there were no significant differences in terms of the overall rate of MACE between both groups (TA group, 8% vs non-TA group, 5.7%; P = .24). Also, no differences were seen in any of the individual adverse events: cardiovascular mortality (TA group, 5.2% vs non-TA group, 3.9%, P = .38), myocardial infarction (TA group, 2.4% vs non-TA group, 3.4%; P = .47), stent thrombo- sis (TA group, 2.4% vs non-TA group, 2.3%, P = .9) or target lesion revascularization (TA group, 4.4% vs non-TA group, 4.8%; P = .85). The incidence of cerebral ischemic events was similar in both groups (TA group, 0.4% vs non-TA group, 0.46%; P = .92). One patient only was diagnosed with transient ischemic attack in the TA group that occurred > 30 days after the pPCI. None of the patients of this group suffered a stroke during follow-up. In the non-TA group, two pati- ents suffered a stroke (one was a ischemic stroke 24 hours after the pPCI and the other one was a hemorrhagic stroke that occurred 3 months after the procedure in a patient treated with triple therapy due to atrial fibrillation). There were no differences in the rate of MACE during the first 24 hours after pPCI (TA group, 1.2% vs non-TA group, 1.4%; P = .88) or at the 1-month follow-up (TA group, 3.6% vs non-TA group, 3.9%; P = .9) (figure 4).

Figure 4. MACE at follow-up. CV, cardiovascular; MACE, major acute cardiovascular events; MI, myocardial infarction; ST, stent thrombosis; TA, thrombus aspiration; TIA, transient ischemic attack; TLR, target lesion revascularization.

DISCUSSION

The main findings of this study are: a) TA is frequently used during pPCI (40.3%), mainly as an initial strategy, with significant differences between the different centers; b) A higher initial TIMI-thrombus grade is the most important predictor for the use of TA; c) TA has a high technical success rate, leading to a significant reduction of the thrombus burden and an improvement of TIMI-flow, facilitating pPCI by allowing more frequently direct stenting; d) TA was not associated with higher rates of cerebrovascular events; and e) The TA was not associated with any differences in the occurrence of MACE during acute phase or at the 1-year follow-up.

The present study analyzes the efficacy and safety of selective TA in the real clinical practice. And this is remarkable for 2 reasons: the most important TA studies4^,7^,9 assessed the routine use of this technique. Performing routine TAs during pPCI is not the standard in clinical practice, where TA is selectively performed in scenarios where it is expected that this technique will be more effective. Also, some of these trials may have a non-negligible sample selection bias6^,7^,9 that may not reflect the actual clinical practice. In our study, the average rate of TA use was around 40.3%. This rate was similar in other nationwide registries.15 The most important predictor for the use of TA was a high initial thrombotic burden.

A key finding of this registry is that TA is effective when it comes to facilitating the pPCI. Unlike other studies, we specifically described thrombotic burden reductions and coronary flow improvements after the TA which, in our opinion, are the most representative effects of the utility of this technique. TA success was achieved in 93.8% of the cases. Since this was not a randomized study, it is not easy to analyze the reduction of no-reflow or the rate of distal embolization with TA. This is so because while trying to reflect real practice TA was used at the discretion of the operator and consequently the TA-group had a higher initial thrombus grade (approximately twice as much) compared to the non-TA group (table 2). It is precisely in patients with a higher thrombotic burden where we can expect higher no-reflow or distal embolization rates. However, probably due to this initial TA that allowed significant reductions of the TIMI-thrombus grade, there were no differences in the rates of no-reflow or distal embolization with the non-TA group that had a lower initial thrombus grade.

Also, patients who underwent TA as an initial strategy had a more than two-fold increase in the rate of direct-stenting compared to those treated conventionally. Beyond the potential economic benefit, direct stenting could be associated with clinical benefits.21

As our study suggests it is possible that the greatest benefit of TA occurs when performed selectively in patients with a higher thrombotic burden. This idea has been suggested in a meta-analysis including the most important TA studies.3 These results must be interpreted with caution since a significant percentage of patients who underwent routine TA did not have significant thrombotic loads. In the TAPAS trial, angiographic thrombi were not observed in 51.4% of cases,4 which also happened in 35% of patients included in the TASTE trial.7 The TOTAL study showed that in up to 90% of patients the thrombus scale ≥ 3.9 Nevertheless, the thrombotic burden was assessed before crossing the culprit lesion with the coronary guidewire which probably lead to overestimating the TIMI-thrombus scale18 as 65% of patients showed TIMI 0 flow. In our own opinion this limits the conclusions drawn from this trial and subsequent subanalyses.22

Beyond the effectiveness of TA, our results support the safety of the technique. The TOTAL study9 described a slight increase in the rate of TA-related strokes. This fact was not consistent with previous trials and ignited and ongoing controversy that still goes on. In our study, there were no significant differences in the stroke rate between both groups. These data are similar to those from the TASTE7^,8 or INFUSE-AMI trial.23 On this regard, TA-related strokes would initially be of ischemic nature, appear during the procedure, and would be evident during the first 24 hours. It is unlikely that hemorrhagic or ischemic strokes occurring > 24 hours after the procedure would have anything to do with this technique.24 In the TOTAL trial,9 the rate of ischemic strokes during the first 48 hours after the procedure was low and did not significantly differ between arms. Also, in the on-treatment and per-protocol analyses the rate of all-cause stroke at 30 days was no significantly different between groups.

Similar to the TA trials most recently published,7^,9 we did not find a significant prognostic benefit associated with TA during the acute phase or at the 1-year follow-up. Despite having repeatedly demonstrated that TA improves reperfusion parameters,4^,9 the lack of an association with any prognostic benefits somehow makes sense. First because it is unlikely that a technical tool, designed to facilitate pPCI, can reduce mortality. Secondly, because the low rate of events described (reported in our cohort as in previous studies) make it difficult for an individual therapy to prove significant reductions of mortality rate. Finally, because mortality depends on many more factors that were not analyzed in our study or in these trials.25

Limitations

This is a retrospective, observational study, with the natural limitations of this design. The exclusion of patients who had a cardiac arrest or underwent bailout PCIs may be indicative of selection bias.

The quantification of thrombotic load according to the previously validated TIMI-thrombus scale may not be accurate due to the design of this tool. We have maintained this classification because it is the most widely used in this setting. However, the degree of thrombus before the TA was assessed after crossing the culprit lesion with the angioplasty guidewire in order to reduce the number of cases with initial TIMI-flow = 0 in which it is impossible to assess the initial TIMI-thrombus grade.

We decided to define TA success when achieving improvements of TIMI-flow grade ≥ 1 or reductions of TIMI-thrombus scale grades ≥ 1 without any immediate complications associated with the technique. However, other parameters of microvascular reperfusion such as the ST-segment elevation resolution or the myocardial blush grade were not measured.

The angiographic coronary flow data are not described after the alternative strategy to perform TA in the non-TA group. This can be a limitation since the immediate results cannot be compared to the TA group. Also, the angiographic analysis was not conducted by an independent core-lab that would have added validity to the results.

The high heterogeneity of the operators involved may have influenced the results seen due to their individual preferences in relation to TA. However, we believe that this may play a favorable role in the external validation of our findings.

CONCLUSIONS

Despite being recently discredited, TA is frequently used in current clinical practice during the pPCI, basically as an initial strategy. A higher initial TIMI-thrombus grade is the most important predictor for the use of selective TA. Selective TA facilitate pPCI by reducing thrombotic burden and improving coronary flow. Selective TA is not associated with with a reduction of MACE neither during the acute phase or at the 1-year follow-up. There is no association of TA with a higher stroke rate.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

 

 

REFERENCES

INTRODUCTION

Primary percutaneous coronary interventions (pPCI) have proven superior to fibrinolytic therapy for the management of patients with ST-segment elevation myocardial infarction (STEMI)1^-3 becoming the treatment of choice in this field.4 However, the question of whether there are any prognostic differences between women and men is still under discussion. Yet despite the fact that in recent studies women exhibit higher mortality rates,5 it is not clear if these differences are associated with worse risk profiles or with a sex-related frailty. Indeed, some studies have not shown any significant relationships between sex and mortality in STEMI, even after adjusting for age and other risk factors.6 Actually, only a limited number of studies have described medium or long-term mortality outcomes and differences in the inclusion criteria (ie, the entire acute coronary syndrome spectrum or only the STEMI subset) and in the therapeutic strategies (ie, medical or interventional) might explain these different findings. The goal of this large, single-center registry was to assess whether in consecutive patients with STEMI undergoing pPCI there were any differences between men and women in the clinical, angiographic, procedural characteristics, and clinical outcome at 30 days or in the long-term.

METHODS

All consecutive patients admitted to our center between January 2006 and December 2016 with a diagnosis STEMI treated with pPCI within 12 hours of symptom onset were recruited. The baseline features (age, sex, burden of cardiovascular risk factors, time from symptoms onset to balloon) were collected along with the procedural characteristics (target vessel, site and type of lesion, pharmacological treatment, thrombus aspiration, type of stent). All interventions were performed following the actual standards of PCI, and the treatment choice was left at the discretion of the operator who performed the procedure. All patients were routinely treated with aspirin (325 mg upon arrival, and then 100 mg daily indefinitely), and an IV bolus of unfractionated heparin (5000 IU). The use of bivalirudin (0.75 mg/kg and 1.75 mg/kg/h at least to the end of the procedure), or unfractionated heparin (100 U/kg or 60 U/kg if abciximab was used) or abciximab was left at the operator’s discretion. When used, the infusion of abciximab was extended for another 12 hours after the procedure. A loading dose of clopidogrel (600 mg), prasugrel (60 mg), or ticagrelor (180 mg) was administered before or immediately after the PCI, unless patients were already on chronic maintenance therapy, and then followed by a maintenance dose of clopidogrel (75 mg once a day), prasugrel (10 mg once a day), or ticagrelor (90 mg twice a day) for 12 months when possible. Repeated revascularization was only performed in the presence of symptom recurrence or proven ischemia related to the treated lesion.

Data on the 30-day follow-up were available for all patients at our center database. Information beyond the first month was collected through outpatient visits, telephone calls or by reviewing any available medical records to obtain the longer follow-up for each patient. All data were entered into a dedicated database.

The men vs women outcomes before and after the propensity score matching were compared. The primary endpoint was long-term mortality after hospital discharge. The secondary endpoint was 30-day mortality rate, 30-day and long-term Bleeding Academic Research Consortium bleeding type ≥ 2.7 Long-term events were evaluated starting from day 31 after discharge until the longer available follow-up. The rate of procedural efficiency (defined a Thrombolysis in Myocardial Infarction [TIMI] III grade flow and residual stenosis < 30%) and ST-segment resolution of more than 50% 60–90 minutes after the PCI was also collected and reported.

Statistical analysis

Quantitative variables were expressed as mean ± standard deviation or median (Q1-Q3), according to the normality of their distribution. Qualitative variables were expressed as frequencies and percentages. The Fisher’s exact test or the chi-square test were used for qualitative variables while the Student’s t test or the Mann-Whitney U test were used for quantitative variables as appropriate. Survival data were represented and analyzed using the Kaplan-Meier curves and the Cox regression analysis. All statistical tests were 2-sided. Results were considered significant if P values < .05. Given the baseline differences between female and male patients and in order to reduce selection bias, we used propensity score matching. The logistic regression model was used based on the baseline and peri-percutaneous coronary intervention characteristics. Thus, P values < .20 were defined to include the selected variables in the final model. The selected variables were age, smoking habit, hypertension, dyslipidemia, diabetes mellitus type 2, obesity, severe chronic renal failure, shock at presentation, cardiac resuscitation at presentation, ejection fraction < 35%, anterior wall myocardial infarct location, femoral access, use of bivalirudin, use of glycoprotein IIb-IIIa inhibitors, percutaneous transluminal coronary angioplasty on the left main coronary artery, use of counterpulsation, thrombectomy, use of drug-eluting stents and total ischemic time. Using these covariates, propensity score was calculated for each patient. Each female patient was matched using 1:1 nearest neighbor matching with a patient from the control group (male) with the same propensity score. The maximum difference (caliper) in the match propensity scores was < 0.15. The standardized mean differences were estimated before and after the matching and balance between both matched cohorts was assessed using the Hotelling T-squared test. Using this technique, 2 comparable groups of 379 patients each were obtained for final analysis. All standardized mean differences after matching were below 10%. Calibration was tested using the Hosmer-Lermeshow test and accuracy was assessed using the area under the ROC curve. Statistical analyses were performed using SPSS 21 statistical software package (IBM software). Propensity score matching was performed using the MatchIt package of R software (version 3.0.2).

RESULTS

From March 2006 to December 2016, among the 1981 patients who underwent pPCIs at our hospital, 484 (24.4%) were females (table 1). Compared to men, women were older (mean age 71.3 ± 11.6 vs 62.9 ± 11.8 years; P < .001), there were fewer female smokers (26.7% vs 72.7%; P < .001), they were more diabetic (28.0% vs 22.3%; P < .002), more hypertensive (69.6% vs 61.3%; P < .001), and they presented more frequently with cardiogenic shock at admission (13.2% vs 9.0%; P= .006). They also had longer symptoms-to-balloon time (5.36 ± 3.97 vs 4.47 ± 3.67 hours; P < .001) and lower left ventricular ejection fractions (46.8 ± 10% vs 48.5 ± 10%; P = .007). Also, as shown on table 2, women were less likely to be treated with glycoprotein IIb-IIIa inhibitors (59.5% vs 71.4%; P < .001), thrombus aspiration devices (48.3% vs 58.0%, P < .001) and stents (79.5% vs 86.6%; P = .01). Procedural efficiency and ST-resolution were significant lower in the female cohort (93.0 vs. 97.1%, P < .001 and 60.0 vs 65.8%, P = .033, respectively, and table 3).

Table 1. Baseline features

		Raw	Matched
	Overall (n = 1981)	Female (n = 484; 24.4%)	Male (n = 1497; 75.6%)	P	Female (n = 379)	Male (n = 379)	P
Age	65.0 ± 12.3	71.3 ± 11.6	62.9 ± 11.8	< .001	68.5 ± 11.9	69.2 ± 11.6	.43
Age > 80 years	262 (13.2)	134 (27.7)	128 (8.6)	< .001	69 (18.2)	75 (19.8)	.58
Diabetes mellitusa	469 (23.7)	135 (27.9)	334 (22.3)	.002	63 (16.6)	74 (19.5)	.29
Hypertensionb	1254 (63.3)	337 (69.6)	917 (61.3)	.001	227 (59.9)	240 (63.3)	.33
Dyslipidemiac	742 (37.5)	182 (37.6)	560 (37.4)	.93	134 (35.4)	142 (37.5)	.54
Obesityd	307 (15.5)	113 (23.3)	194 (13.0)	< .001	64 (16.9)	66 (17.4)	.85
Chronic kidney failuree	53 (2.7)	17 (3.5)	36 (2.4)	.19	23 (6.1)	23 (6.1)	1.00
Smoking (current or former smoker)	1217 (61.4)	129 (26.7)	1088 (72.7)	< .001	129 (34.0)	129 (34.0)	1.00
Cardiogenic shock at presentation	198 (10.0)	64 (13.2)	134 (9.0)	.006	56 (14.8)	43 (11.3)	.16
Oral intubation	116 (5.9)	31 (6.4)	85 (5.7)	.56	26 (6.9)	23 (6.1)	.66
Cardiac resuscitation at presentation	21 (1.1)	8 (1.7)	13 (0.9)	.14	7 (1.8)	8 (2.1)	.79
Left ventricular ejection fraction (%)	48.4 ± 10.0	46.8 ± 10.0	48.5 ± 10.0	.007	47.5 ± 9.4	47.3 ± 9.6	.83
Left ventricular ejection fraction < 35%	202 (10.2)	69 (14.3)	133 (8.9)	.001	43 (11.3)	44 (11.6)	.91
Total ischemia time	4.7 ± 3.8	5.4 ± 4.0	4.5 ± 3.7	< .001	4.4 ± 3.7	4.6 ± 4.0	.13
Anterior wall infarct location	877 (44.3)	217 (44.8)	660 (44.1)	.82	165 (43.5)	165 (43.5)	1.00
a American Heart Association Guidelines definition. b Arterial systemic pressure ≥ 140/90 mmHg. c Total cholesterol ≥ 200 mg/dL; low density lipoproteins ≥ 130 mg/dL; triacylglycerol ≥ 175 mg/dL. d Body mass index > 30. e Dialysis o serum creatinine > 2 mg/dL. Values are expressed as mean ± standard deviation or frequencies (percentages).

Table 2. Angiographic and periprocedural features

		Raw	Matched
	Overall (n = 1981)	Female (n = 484; 24.4%)	Male (n = 1497; 75.6%)	P	Female (n = 379)	Male (n = 379)	P
Multivessel disease	1055 (53.3)	259 (53.5)	796 (53.2)	.90	194 (51.2)	195 (51.5)	.94
Graft disease	6 (0.3)	2 (0.4)	4 (0.3)	.62	1 (0.3)	2 (0.5)	.56
Radial access	371 (18.7)	82 (16.9)	289 (19.3)	.25	58 (15.3)	57 (15.0)	.92
Use of GP IIb-IIIa	1357 (68.5)	288 (59.5)	1069 (71.4)	< .001	251 (66.2)	242 (63.9)	.49
Bivalirudin	210 (10.6)	61 (12.6)	149 (9.9)	.12	35 (9.2)	45 (11.9)	.24
Multivessel PCI	93 (4.7)	25 (5.2)	68 (4.5)	.57	20 (5.3)	18 (4.7)	.74
PCI on left main coronary artery	64 (3.2)	17 (3.5)	47 (3.1)	.69	13 (3.4)	13 (3.4)	1.00
Aortic counterpulsation	251 (12.7)	69 (14.3)	182 (12.2)	.23	57 (15.0)	49 (12.9)	.40
Thrombus aspiration	1102 (55.6)	234 (48.3)	868 (58.0)	< .001	203 (53.6)	193 (50.9)	.47
Stent implantation	1682 (84.9)	385 (79.5)	1297 (86.6)	.01	314 (82.9)	318 (83.9)	.58
Drug-eluting stent implantation	832 (42.0)	194 (40.0)	658 (43.9)	.09	148 (39.0)	152 (40.1)	.77
Values are expressed as mean ± standard deviation or frequencies (percentages). GP, glycoprotein; PCI, percutaneous coronary intervention.

Table 3. Outcomes

		Raw	Matched
	Overall (n = 1981)	Female (n = 484; 24.4%)	Male (n = 1497; 75.6%)	P	Female (n = 379)	Male (n = 379)	P
Procedural efficacy	1903 (96.1)	450 (93.0)	1453 (97.1)	< .001	342 (90.2)	358 (94.4)	.039
ST-segment resolution > 50%	1086 (64.4)	243 (60.0)	843 (65.8)	.033	180 (47.5)	205 (54.1)	.07
30-day BARC bleeding type ≥ 2	27 (2.1)	22 (4.5)	21 (1.4)	.002	16 (4.2)	6 (1.6)	.007
Long-term BARC bleeding type ≥ 2	41 (2.1)	21 (4.3)	20 (1.3)	< .001	13 (3.4)	7 (1.8)	.257
30-day mortality rate	103 (5.2)	43 (8.9)	60 (4.0)	< .001	36 (9.5)	21 (5.5)	.039
Overall mortality at long-term follow-up	390 (19.7)	115 (23.8)	275 (18.4)	.01	97 (25.6)	81 (21.4)	.170
Values are expressed as frequencies (percentages). BARC, Bleeding Academic Research Consortium.

At the 30-day and long-term follow-up (mean 4.9 ± 3.2 years, completed in 1634, 82.5% patients) the female sex was associated with a higher mortality rate (8.9% vs 4.0%, P < .001 and 23.8% vs 18.4%, P = .01, respectively) and a higher rate of major bleedings at 30 days (4.5% vs 1.4%; P = .002).

After propensity score matching, 379 men and 379 women were selected. The baseline and peri-procedural characteristics of the propensity-matched pairs were identical (table 1, table 2, figure 1, figure 2, and table 1 and table 2 of the supplementary data). In this cohort, female sex continued to be associated with a lower procedural efficiency (94.4% vs 90.2%; P = .039) and a higher rate of major bleedings and death at 30 days (9.5% vs 5.5%, P = .039 and 4.2% vs 1.6%, P = .007). Conversely, in the matched cohort no significant differences were found in the long-term mortality rate among survivors (25.6% vs 21.4%, P = .170, table 3; and log-rank P = .23, figure 3). The multiple Cox regression analysis revealed that age (hazard ratio [HR], 1.09; (1.06 – 1.12); P < .001), cardiogenic shock at presentation (HR, 6.82 (3.84 – 12.12); P < .001), the left ventricular ejection fraction < 35% (HR, 1.98 (1.11 – 3.54); P = .022) and procedural efficacy (HR, 0.46 (0.23 – 0.89); P = .022) have an effect on mortality when included together with female sex (HR, 0.68 (0.42 – 1.09); P = .106), which is not significant as stated before (table 4).

Figure 1. Distribution of propensity scores. Propensity score goes between 0 and 1 and several variables are included in its estimation. It serves as a tool for measuring the similarities among patients. Therefore, matched female and male patients show similar distributions of propensity scores and a wide range, covering all types of patients. Unmatched propensity score units lay on opposite extremes, as expected.

Figure 2. Distribution of propensity score before and after the matching.

Figure 3. Kaplan-Meier curve for long-term mortality based on sex. There is no difference on the long-term mortality rate between female and male patients in the matched population.

Table 4. Multiple regression analysis

	HR (95%CI)	P
Female sex	0.68 (0.42 – 1.09)	.106
Age	1.09 (1.06 – 1.12)	< .001
Cardiogenic shock at presentation	6.82 (3.84 – 12.12)	< .001
Left ventricular ejection fraction < 35%	1.98 (1.11 – 3.54)	.022
Procedural efficacy	0.46 (0.23 – 0.89)	.022
Cox proportional hazard model for overall mortality at long term follow-up. 95%CI, 95% confidence interval; HR, hazard ratio.

Main outcome analysis was performed based on a 2-time period (2006-2010 and 2011-2016) without underlining any differences among the groups (table 2 of the supplementary data).

DISCUSSION

Our large single-center registry showed that in a high PCI volume center, women admitted with STEMI undergoing pPCI have a higher 30-day and long-term mortality rate compared to men. This difference persists after propensity score adjustment regarding the 30-day mortality.

A drop in cardiovascular mortality has been observed over the last few decades, but cardiovascular disease is still the leading cause of mortality in women worldwide. Cardiovascular mortality remains higher in women compared to men.5 So far, the reasons of this difference have been mainly justified by the higher prevalence of traditional risk factors (higher mean age, hypertension, diabetes, and renal failure) in the female cohort.6 Also, women who experience myocardial infarction often present with atypical symptoms like dyspnea, fatigue, nausea/vomiting and atypical chest pain, which can lead to delayed diagnosis and treatment.8 Another factor associated with a higher mortality rate to be taken into account is represented by bleeding and mechanical complications, more common in women compared to men.9^-11 Our study confirmed all these data: in our population, women were significantly older, with more traditional risk factors (except for smoking), longer ischemic time frames and higher-risk presentations. Also, they had a significantly higher rate of bleeding and mechanical complications.

After propensity score adjustment, out study showed that female sex was independently associated with 30-day but not long-term mortality. These findings are similar to those of a recent large meta-analysis led by Conrotto et al.,12 that included 98 778 patients (73 559 men and 25 219 women) and could be explained, at least in part, by the different pathophysiology of coronary disease in women: the rupture of the plaque surface, the leading cause of coronary occlusion in men, happens only in around 50% of women,13 the remaining percentage being represented by the erosion of the plaque,14 coronary spasm leading to thrombus generation,15 and spontaneous coronary artery dissection.16 Particularly spontaneous coronary artery dissection seems to play an important role in younger women (< 60 years of age) and is associated with a high rate of major adverse cardiac events.17 Therefore, these findings may explain why, in our population, women had lower rate of thrombus aspiration, use glycoprotein IIb-IIIa inhibitors, and stent implantation, which in turn may justify, along with the clinical features, the lower procedural success and ST-segment resolution observed in our study. These factors, associated with the higher rate of bleedings and mechanical complications and other psychological factors, like depression, more prevalent in women compared to men in the general population,18^,19 may be phenotypes of a higher frailty in the female sex, and may definitely explain the worse outcomes, at least in the short-term. At long-term, other factors, like the lower in-stent restenosis rate and the resulting lower need for target vessel revascularization observed in women, and already shown in some studies,20^-23 may explain the similar outcomes observed in the propensity score analysis.

Limitations

This study has some important limitations; first, even though is a retrospective analysis, it is based on a prospective and dedicated database with propensity score matched analysis. Secondly, data are derived from a single center, which limits their applicability. For example, the use of drug-eluting stents was lower than it is actually is, mainly because the time frame of the study is wide. Actually, from 2006 to 2010 the percentage of drug-eluting stents was about 15% while during the second period (2011-2016), we found 65% of cases with drug-eluting stent implantation. Finally, due to the time frame of the data collection, most procedures were performed via femoral artery access, so we can assume that radial access could have lowered the rate of access bleeding complications, but we need further randomized studies targeted at the female population before being able to validate this hypothesis. However, this is probably a representative sample of an all-comers STEMI population who undergo pPCI in the real world.

CONCLUSIONS

In conclusion, in our single-center cohort of patients and after propensity score adjustment, women with STEMI undergoing pPCI seem to have a higher 30-day mortality rate but similar long-term outcomes after discharge compared to men. Even if residual confounding cannot be ruled out, this difference in the outcomes may be partially explained by biological sex-related differences.

CONFLICT OF INTERESTS

None of the authors have declared any conflicts of interests related to the present article.

 

 

REFERENCES