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

INTRODUCTION

The STENTYS Xposition S (STENTYS S.A., Paris, France) is a sirolimus-eluting self-expanding nitinol stent designed to adapt its size to the vessel diameter and facilitate its complete apposition when exerting chronic strength towards the outside. It has long been confirmed that one of the most important factors of stent thrombosis is the incorrect apposition of the stent.1 The characteristics of this stent make it especially useful to revascularize acute coronary syndromes (ACS), especially ST-segment elevation acute coronary syndromes with lesions with high thrombotic load. Also, a potential benefit in ectatic coronary vessels and lesions with great proximal and the distal diameter mismatch has been confirmed, bifurcations (left main coronary artery [LMCA] included), and venous grafts.

The objective of this study was to assess the benefit of this stent in the routine clinical practice by analyzing the type of lesions this stent is used with and the immediate angiographic results and at the clinical follow-up.

METHODS

A cohort of consecutive patients treated with the STENTYS Xposition S stent was analyzed from January 2018 through October 2019 in a tertiary hospital where over 1000 percutaneous coronary interventions are performed each year. All coronary lesions were quantified using a quantitative coronary angiography. Lesions in vessels with changes in size (ectasia or proximal-distal diameter mismatch of the lesion), in a bifurcation, in the presence of a high thrombotic load or in a venous graft were analyzed. The interventional strategy to be followed, imaging modalities included, was left to the operator’s criterion. The clinical and follow-up data were obtained from the electronical clinical records of the healthcare system of our autonomous community. All events were defined in a standard way according to the Academic Research Consortium-2 (ARC-2) consensus document.2

Patients' informed consent was obtained to the interventional procedure and, subsequently, verbal informed consent was given during the follow-up.

The data analysis was conducted using the IBM SPSS 20.0 statistical software package. Continuous variables were expressed as mean ± standard deviation or median with interquartile range depending on whether they followed a normal distribution or not, respectively. Qualitative variables were expressed as relative percentage. The cumulative incidence of events at the follow-up was estimated.

RESULTS

From January 2018 through September 2019, 1692 percutaneous coronary interventions with stent implantation were performed. The STENTYS Xposition S stent was used in 50 patients (62 lesions). The patients’ median age was 66 years [49-92]. Eighty-eight per cent of the patients were males. Table 1 shows the clinical characteristic of patients and coronary lesions. The most common clinical presentation was ST-segment elevation acute coronary syndrome in 23 patients (46%) followed by non-ST-segment elevation acute coronary syndrome in 22 patients (44%), and stable angina in 5 patients (10%). According to the classification established by the American College of Cardiology/American Heart Association the most common type of lesion was B1 lesion (38.7%). The right coronary artery was the most frequently treated vessel in 33 patients (53.2%).

Table 1 Clinical characteristics of patients and angiographic characteristics of the lesions

Patients (N)	50
Age (years)	66.6 (49-92)
Males	44 (88%)
Arterial hypertension	33 (66%)
Body mass index (kg/m2)	27.9 ± 4.9
Dyslipidemia	32 (64%)
Diabetes mellitus	12 (24%)
Smoking	27 (54%)
Family history of ischemic heart disease	3 (6%)
Peripheral vasculopathy	3 (6%)
Atrial fibrillation	6 (12%)
Chronic pulmonary disease	6 (12%)
Kidney disease	6 (12%)
Stable angina pectoris	5 (10%)
NSTEACS	22 (44%)
STEACS	23 (46%)
Lesions (N)	62
Lesion length (mm)	14.56 ± 3.64
Reference diameter (mm)	4.1 ± 0.8
Percent stenosis. QCA (%)	70.08 ± 17
Location of the lesion
Left main coronary artery	3 (4.8)
Left anterior descending coronary artery	11 (17.7)
Left circumflex artery	15 (24.2)
Right coronary artery	33 (53.2)
Classification of the lesion
A	0
B1	24 (38.8)
B2	19 (30.6)
C	19 (30.6)
Indication for STENTYS
Ectasia. Proximal-distal diameter mismatch	45 (72.6)
Bifurcation	17 (27.4)
Provisional stenting technique	15 (88.2)
Double stent technique	2 (11.8)
NSTEACS, non-ST-segment elevation acute coronary syndrome; QCA, quantitative coronary angiography; STEACS, ST-segment elevation acute coronary syndrome. Kidney damage: glomerular filtration rate < 60 mL/min/1.73 m2. Data are expressed as N (%) o mean ± standard deviation.

Ectasia and great proximal-distal diameter mistmatch at the lesion were the main indication for the use of this stent, in 72.6% of the lesions, with a mean vessel reference diameter of 4.1 mm ± 0.8 mm. A certain size was required to use this type of stent. The percutaneous coronary interventional on a bifurcation was the second most common indication, in 27.4% of the patients (2 of them on the LMCA). The most common type of bifurcation according to the Medina classification was 1-1-0, in 9 cases (52.9%). The secondary branch was damaged in 17% of the patients. The provisional stenting technique was the most widely used in 15 cases (88.2% of bifurcations) re-crossing to the secondary branch in 9 of them (60%). The dilatation of the secondary branch only occurred in 7 patients and only in the other 2 stents were implanted: one in a 0-1-1 bifurcation according to the Medina classification (minicrash technique) and the other in a 1-1-1 bifurcation according to this classification (TAP technique [T-and protrusion technique]). In both cases the STENTYS Xposition S stent was implanted in the main vessel and a non-self-apposing stent in the secondary branch (figure 1).

Figure 1. A: lesion with significant thrombotic load in the mid right coronary artery, which remains after thrombus aspiration. B: 3.5-4.5 mm × 27 mm Xposition S direct stent implantation. C: final angiographic result. D: significant stenosis in distal left main coronary artery. E: 3-3.5 mm × 27 mm Xposition S stent implantation from the proximal left main coronary artery to the left anterior descending coronary artery. F: angiographic result after postdilatation.

A high thrombotic load (Thrombolysis in Myocardial Infarction flow grade 4-5) was seen in 8 lesions. All of them in ectatic coronary vessels or with proximal-distal caliber mismatch. No case of venous graft treated with STENTYS was reported.

Predilatation occurred in 32 lesions (51.6%) and postdilatation in 37 (59.7%). The criterion used for postdilatation was angiography guided visual underexpansion. Intravascular ultrasound was performed in 15 patients (30%) before the implant. It was also used in 2 patients to optimize the percutaneous coronary intervention given the persistent stent underexpansion seen on the angiography. In both cases the minimum lumen area was > 5.5 mm2 with stent expansion > 80% and lack of incomplete apposition (defined as a strut separation of > 0.4 mm axial and 1 mm longitudinal) (figure 2). The optical coherence tomography was performed in a patient with ST-segment elevation acute coronary syndrome before and after the implant. It revealed a high thrombotic load with lack of immediate stent malapposition.

Figure 2. A: acute thrombotic occlusion in left circumflex artery with Thrombolysis in Myocardial Infarction flow grade 0. B: the intravascular ultrasound shows a great deal of thrombus in the lesions despite thrombus aspiration. C: implantation of 2 3.5-4.5 mm × 27 mm Xposition S overlapping stents. D: the intravascular ultrasound performed after stent implantation confirms the good angiographic results and lack of stent malapposition.

Angiographic success was achieved (with the stent properly implanted, a residual lesion ≤ 10%, and Thrombolysis in Myocardial Infarction flow grade 3) in all patients but 1, in whom stent implantation failed in a severely calcified LMCA lesion. In this case, predilatation was first attempted using a conventional balloon and then a cutting balloon on the LMCA severe distal lesion. A 3.3-4.5 mm × 22 mm STENTYS Xposition S stent was implanted with stent loss during retrieval, which remained braced to the guide catheter. Afterwards, a balloon-expandable drug-eluting stent was successfully implanted. The un-crimped stent was retrieved by crossing a guidewire from the femoral access through the stent distal struts. It was finally captured with a snare.

The median score obtained in the PRECISE-DAPT risk calculator (Predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy) was 16.5 (7-25), and the median score obtained in the DAPT index (Dual antiplatelet therapy) was 1.15 (−2-4). Ticagrelor was the most commonly used P2Y₁₂ inhibitor (58.1%). A 12-month course of dual antiplatelet therapy was prescribed in 48 patients (96%).

After a median follow-up of 373 days (256-439), 1 patient had an acute myocardial infarction 3 months after the intervention. However, the coronary angiography did not reveal coronary artery disease progression but confirmed the good results of the previous intervention. An 84-year-old woman died at admission due to heart failure. Three patients died of non-cardiac causes: 1 due to septic shock at admission, the other patient died 6 months after the percutaneous coronary intervention due to high-grade lymphoma, and the third one 4 months after the percutaneous coronary intervention due to lung cancer. No cases of definitive stent thrombosis or revascularization of the treated lesion were reported. No bleeding was seen either at the follow-up.

DISCUSSION

This type of stent is not widely used in our setting and we believe 2 are the reasons why. The first one is the need for a learning curve to know how to handle this implant. In former iterations of the device, the delivery system had some technical limitations like the jumping phenomenon that could occur right when the sheath was being released due to the elastic properties of nitinol. Unlike its predecessor (STENTYS sirolimus DES), the stent of the new STENTYS Xposition S system, is mounted over a semicompliant balloon and covered by a 0.0032 in-thick sheath. The reason for balloon inflation is not to dilate the stent, but to rupture the external sheath from the distal to the proximal border to allow a proper vessel-wall stent apposition. This has reduced the complexity of the release mechanism.3 However, we should remember that after the implant, the retrieval of both the balloon and the device sheath should be conducted with care by separating the guide catheter from the ostium to avoid deep intubation. The other reason that may explain why this stent is still not widely used can the augmented profile of the device and its rigidity, which both reduce its navigational and crossing capabilities compared to balloon-expandable stents.

Due to the characteristics of the stent and the experienced gained using it, the clinical settings where it can be useful are: ectatic vessel, since the stent reaches 6.5 mm of diameter with the device L size; proximal and distal diameter mismatch due to its adaptative capabilities to the vessel caliber; lesions with high thrombotic load, since this stent self-expanding capabilities facilitate its expansion until it reaches the vessel wall if thrombus reabsorption occurs, which avoids late stent malapposition; and bifurcations with ostial damage and 30º to 70° angles. The stent z-shaped mesh and the presence of small interconnectors facilitate re-crossing the lateral branch and disconnecting the struts without having to use the final kissing balloon technique. Thanks to its self-expanding capabilities, the unconnected struts cover the lateral branch ostium making the double stent technique unnecessary on many occasions.

In the studies published on former iterations of the device, the self-expanding stent proved superior to the balloon-expandable stent regarding better apposition. The randomized APOSSITION II clinical trial,4 conducted among patients with acute myocardial infarction, showed a lower rate of stent malapposition (defined as > 5% of struts per patient as seen on the optical coherence tomography) 3 days after the primary percutaneous coronary intervention. The APOSSITION IV clinical trial,5 also conducted among patients with acute myocardial infarction, showed a significantly lower percentage of stent malapposition at the 4-month follow-up in patients treated with self-expanding stents compared to patients treated with balloon-expandable stents (0.07% vs 1.16%; P = .002). However, no inter-group differences were found at the 9-month follow-up (0.43% vs 0.28%; P = .55) or in the rate of major adverse cardiovascular events (MACE). The clinical repercussions of this improvement in the early apposition of the stent has not been studied thoroughly. The APOSSITTION III trial6 showed that the use of STENTYS BMS in the percutaneous coronary intervention setting was associated with acceptable cardiovascular results at the 2-year follow-up, an overall rate of MACE of 11.2%, and a rate of stent thrombosis of 3.3%. We should mention that this study revealed a significant reduction of adverse events after the systematic implementation of a standard protocol (predilatation, implantation, postdilatation). The data available support the hypothesis of the need for mild postdilatation to avoid early complications probably because the stent does not have enough radial strength to achieve a proper expansion in rigid often calcified lesions, especially when predilatation is not fully effective. Therefore, postdilatation would avoid the incomplete expansion of the stent, which may increase the risk of stent thrombosis.7

Our study with the STENTYS Xposition S stent reached angiographic success in 98.4% of the cases, although we should remember that, from the anatomical point of view, they were not complex lesions (only 30% were type C lesion). Stent implantation failed in 1 severely calcified LMCA lesion; it is precisely in this type of lesions where its use is ill-advised, especially if predilatation is not effective.8

Regarding its use in bifurcations the studies published to this day have also discussed a former iteration of this device with good results. In the observational, multicenter, and prospective OPEN II trial,9 the rate of MACE at the 12-month follow-up was 13% (10.1% at 6 months). This rate of events was basically due to the need for revascularization of the treated lesion, while the rate of stent thrombosis at the 12-month follow-up was 1%. We should also mention that the kissing balloon technique was only used in 21.7% of the patients. Also, there were no significant differences in the rate of MACE between patients in whom the kissing balloon technique was used and those in whom it was not used.9

To this day, the only study published on the new STENTYS Xposition S model is the TRUNC, a prospective and multicenter study that assessed the efficacy and safety profile of this type of stent in the LMCA. Angiographic success was achieved in 96.6% of the patients and the overall rate of MACE was 8.3% at the 12-month follow-up, basically due to revascularization of the lesion treated in 5.4%.10 Here we should mention the preliminary results reported by the SIZING (Worldwide every-day practice registry assessing the Xposition S self-apposing stent in challenging lesions with vessel diameter variance) and WIN (World-wide registry to assess the STENTYS Xposition S for revascularization of coronary arteries in routine clinical practice) registries. Both registries confirm the safety and efficacy profile of the current iteration of the stent in the routine clinical practice.

Limitations

Our study has several limitations. Because of its retrospective, single-center nature and the limited number of cases involved, we cannot draw definitive conclusions on the device safety and efficacy profile. No intracoronary imaging modality was performed systematically to guide the implant, which may have been useful, especially the optical coherence tomography. However, we believe that this study is relevant due to the scarce evidence available on the last iteration of this stent.

CONCLUSIONS

In our series of lesions located in ectatic vessels or with proximal-distal diameter mismatch and in bifurcations, the STENTYS Xposition S stent is a good therapeutic alternative that achieves good immediate angiographic results and good mid-term clinical results.

FUNDING

No funding to declare.

AUTHORS' CONTRIBUTIONS

Data collection: A. Pérez Guerrero, I. Caballero Jambrina. Data analysis: A. Pérez Guerrero, G. Fuertes Ferré, I. Caballero Jambrina, G. Galache Osuna, M.C. Gracia Ferrer. Analysis and interpretation of data: A. Pérez Guerrero, G. Fuertes Ferré, J. Sánchez-Rubio, G. Galache Osuna, M.C. Gracia Ferrer. Critical review of manuscript: J.A. Diarte de Miguel, M.R. Ortas Nadal.

CONFLICTS OF INTEREST

None declared.

REFERENCES

INTRODUCTION

The physiological assessment of coronary lesions is a routine practice in contemporary cath labs and is strongly recommended by the European guidelines to guide the percutaneous coronary intervention (PCI) decision-making process.1 Unlike fractional flow reserve, the new instantaneous wave-free ratio (iFR) index allows us to analyze the physiological significance of each lesion and each coronary segment.2-5 This has led to the creation of the new and specific SyncVision software package (SyncVision version 4.1.0.5, Philips Volcano, Belgium), that shows the functional compromise of each lesion and predicts the expected iFR improvement after percutaneous treatment.3,4

Few observational studies published have analyzed the reduction in the length of the stent implanted compared to angiography-guided revascularization in long and diffuse coronary lesions.4,5 However, this reduction could be detrimental to the complete coverage of the plaque in this type of lesions, which has proven to be a predictor of major adverse cardiovascular events at the follow-up.6

The objective of our study is to analyze the utility of the iFR and SyncVision software to guide the PCI decision-making process in long, sequential, and diffuse coronary lesions.

METHODS

We have designed a multicenter, randomized, controlled, and open-label trial to compare SyncVision/iFR-guided revascularization to angiography-guided revascularization in patients with long, sequential or diffuse significant angiographic coronary lesions (ClinicalTrials.gov identifier: NCT04283734). All the variables that will be analyzed during the study are shown on table 1.

Table 1. Variables that will be analyzed during the study

Nº	Variable	Expressed as
Personal medical history
1	Sex (men/women)	no. (%)
2	Age (years)	no. ± SD
3	Hypertension	no. (%)
4	Diabetes mellitus	no. (%)
5	Dyslipidemia	no. (%)
6	Former smoker	no. (%)
7	Previous ischemic cardiomyopathy	no. (%)
8	Previous revascularization	no. (%)
9	Atrial fibrillation	no. (%)
10	Heart failure	no. (%)
11	Previous stroke	no. (%)
12	Peripheral artery disease	no. (%)
13	Previous significant bleeding	no. (%)
14	Basal hemoglobin levels (mg/dL)	no. ± SD
15	Basal creatinine levels (mg/dL)	no. ± SD
16	Left ventricular ejection fraction (%)	no. ± SD
17	Clinical presentation (stable angina/NSTEMI/STEMI)	no. (%)
18	Baseline ultra-sensitive troponin levels (ng/L)	no. ± SD
Procedural data
19	Arterial access (radial/femoral/other)	no. (%)
20	P2Y12 inhibitor preload	no. (%)
21	IIb/IIIa inhibitor use during the procedure	no. (%)
22	Multivessel disease	no. (%)
23	Syntax score	no. ± SD
24	Randomized vessel (LAD/LCx/RCA/other)	no. (%)
25	Vessel lesion length (mm)	no. ± SD
26	Vessel reference diameter (mm)	no. ± SD
27	Vessel stenosis (%)	no. ± SD
28	Total stent length as seen on the angiography (mm)	no. ± SD
29	Total length of the stent implanted (mm)	no. ± SD
30	Differences between stent length estimated and implanted (mm)	no. ± SD
31	Stent diameter (mm)	no. ± SD
32	Optimal angiographic result (final TIMI III flow, absence of dissections and residual stenosis < 20%)	no. (%)
33	Contrast (milliliters)	no. ± SD
34	Use of intracoronary imaging	no. (%)
35	Use of rotablation	no. (%)
36	Procedural complications (no reflow/ dissection/acute vessel closure/perforation/other)	no. (%)
37	Baseline iFR in the intervention group	no. ± SD
38	Diffuse improvement of iFR by SyncVision	no. (%)
39	Estimated stent length to achieve an iFR > 0.89 (mm)	no. ± SD
40	Final iFR in the intervention group	no. ± SD
41	Need to implant an additional stent	no. (%)
Hospitalization data
42	Bleeding complications	no. (%)
43	Ultra-sensitive troponin peak levels (ng/L)	no. ± SD
44	Periprocedural myocardial infarction	no. (%)
45	In-hospital death	no. (%)
46	In-hospital stroke	no. (%)
47	In-hospital stent thrombosis	no. (%)
Pharmacological treatment at discharge
48	Aspirin	no. (%)
49	P2Y12 Inhibitor (no/clopidogrel/ticagrelor/prasugrel)	no. (%)
50	Anticoagulation (no/acenocumarol/rivaroxaban/ dabigatran/apixaban/edoxaban)	no. (%)
51	Beta-blockers	no. (%)
52	ACEI/ARB/ARNI	no. (%)
53	Calcium antagonists	no. (%)
54	Other anti-ischemic drugs	no. (%)
Follow-up visits (after 3, 6, and 12 months)
55	Bleeding complications	no. (%)
56	Dual antiplatelet therapy	no. (%)
57	Anticoagulation (no/acenocumarol/rivaroxaban/ dabigatran/apixaban/edoxaban)	no. (%)
58	Probable or definitive stent thrombosis	no. (%)
59	Spontaneous myocardial infarction	no. (%)
60	New target lesion revascularization	no. (%)
61	New target vessel revascularization	no. (%)
62	Revascularization of other vessel	no. (%)
63	Death	no. (%)
64	Cause of death (cardiac/non cardiac)	no. (%)
65	Stroke	no. (%)
66	Beta-blockers	no. (%)
67	ACEI/ARB/ARNI	no. (%)
68	Calcium antagonists	no. (%)
69	Other anti-ischemic drugs	no. (%)
70	Residual angina (I/II/III/IV)	no. (%)
71	Withdrawal from the study	no. (%)
72	Lost to follow-up	no. (%)
ACEI, angiotensin-converting-enzyme inhibitors; ARB, angiotensin receptor blockers; ARNI, angiotensin receptor blocker and neprilysin inhibitor; LAD, left anterior descending coronary artery; LCx, left circunflex artery; RCA, right coronary artery; SD, standard deviation; TIMI, Thrombolysis in Myocardial Infarction. NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction.

 

Additionally, the study has received the proper ethical oversight and has been approved by the Ethical Comitee of Córdoba.

Inclusion and exclusion criteria

Patients with the following criteria are being included: a) patients > 18 years old who require percutaneous coronary treatment due to ischemia (silent, stable angina or acute coronary syndrome); b) presence of a vessel with sequential lesions separated by < 10 mm from each other with a total lesion length > 25 mm and a percent diameter stenosis > 60% (as seen on the quantitative coronary angiography assessment) in, at least, 1 segment; or a coronary segment > 30 mm with diffuse disease, and a percent diameter stenosis > 60% (as seen on the quantitative coronary angiography assessment) in, at least, 1 region; c) baseline iFR ≤ 0.89 distal to a potentially randomizable lesion.

We have stablished the following exclusion criteria: a) patients with acute coronary syndrome with non-optimal results in the culprit vessel (final Thrombolysis in Myocardial Infarction (TIMI) flow grade < III, non-reflow phenomenon during treatment, residual coronary dissection, lost or compromise of a major side branch); b) patients with acute coronary syndrome and left ventricular ejection fraction < 45%; c) life expectancy < 12 months; d) patients with severe aortic stenosis; e) contraindication for dual antiplatelet therapy for at least 12 months; f) presence of significant thrombocytopenia (< 10 x 109/L); g) patients with an indication for bypass surgery according to the heart team; h) pregnancy; i) inability to understand the informed consent.

Endpoints

The study primary endpoint is the reduction of the average length of the stent implanted in the SyncVision-guided group measured in millimeters (mm) compared to the angiography-guided group. The study secondary endpoint is a composite of cardiac death, myocardial infarction, definitive or probable stent thrombosis, new target lesion revascularization or new target lesion failure (major adverse cardiovascular events [MACE]); and the assessment of residual ischemia through single-photon emission computed tomography at the 6-month follow-up.

Procedure

After the diagnostic phase, the use of intracoronary vasodilators is mandatory to exclude possible coronary spasms. Lesions will be assessed by 2 expert operators (prior to randomization) to determine the coronary segment to treat when the revascularization is angiography-guided based on current routine clinical practice. Afterwards, the iFR will be determined at baseline. If the obtained iFR is ≤ 0.89, patients will be randomized to the angiography-guided revascularization group (the control group) or to the iFR pullback-guided revascularization group using the SyncVision software (figure 1). Intracoronary imaging can be used in both groups based on the operator’s criteria to optimize the angiographic result.

Figure 1. Summary of randomization, treatment targets, and follow-up of the iLARDI study. iFR, instantaneous wave-free ratio; MACE, major adverse cardiovascular events; PCI, percutaneous coronary intervention.

In the intervention group, a pressure wire (Verrata pressure guidewire, Philips Volcano, Belgium) will be inserted trough a guide catheter towards the vessel ostium to normalize the pressure between the aortic and the vessel ostium. Secondly, the pressure wire will be advanced distally to the lesion. Under stable hemodynamic conditions (without the administration of vasodilators), we will determine the baseline iFR. Afterwards, the wire will be removed under continuous fluoroscopy, and in the same projection. If the iFR at the vessel ostium is 1 ± 0.02, the absence of drift will be confirmed and an angiogram in the same angiographic position will be performed. The SyncVision software can recognize the vessel analyzed and identify the physiological contribution of every lesion and every segment, predicting the improvement of the iFR after treatment. The iFR improvement is depicted as yellow dots. Each yellow dot represents an iFR improvement of 0.01 if that zone was percutaneously treated. The accumulation of many yellow dots suggests that the contribution of that lesion to physiological compromise is high. After performing the physiological assessment of each lesion, the operator would have to treat the minimum segment needed to achieve an iFR of 0.90. Cases without an accumulation of dots have been considered as physiological diffuse disease (defined as the presence of < 20% of the total number of dots) in the coronary segment physiologically assessed. Those cases will be medically treated due to the theoretical absence of benefit of the percutaneous treatment (figure 2 and figure 3).

Figure 2. Flowchart of technical treatment details of patients randomized to the intervention group.

* We consider as optimization the postdilatation of the previous stented area if an in-stent accumulation of yellow dots is seen; or the percutaneous treatment of a new segment with physiological compromise not seen in the baseline iFR-pullback study. iFR, instantaneous wave-free ratio.

Figure 3. Image of iFR co-registration using the SyncVision software in a patient included in the study and randomized to the intervention group with a diffuse lesion in the left anterior descending coronary artery, and the physiological contribution of every segment. The estimated length of the stent to achieve an iFR > 0.89 is 50.6 mm.

Follow-up

Patients will be followed either through phone calls or physical examination at the 3, 6 and 12-month follow-up. At the 6-month follow-up a stress single-photon emission computed tomography (physiological or pharmacological) will be performed in all patients. The composite of cardiovascular death, definitive or probably stent thrombosis, new target lesion failure or new target lesion revascularization will be considered as MACE.

Quantitative coronary measurements

Quantitative coronary measurements will be performed using a validated system (CAAS system, Pie Medica Imaging, Netherlands). The measurements analyzed will be the vessel reference diameter, the vessel minimal lumen diameter, and the percentage of stenosis. All measurements will be taken at baseline and after the PCI.

Statistical analysis

Regarding the statistical analysis, quantitative variables will be expressed as mean ± standard deviation and qualitative variables as absolute numbers and percentages. To determine the relationship among quantitative variables, we will be using the paired Student t test for paired data. To determine the relationship among the qualitative ones, we will use the chi-squared test. In all cases, differences will be considered significant with P values < .05. We will be using the IBM SPSS Statistics software package (version 24.0 for Macintosh, SPSS Corp., United States). To calculate the sample size, we have performed a retrospective analysis of the last 20 patients who were treated at our centre and showed a sequential or diffuse lesion in the coronary vessel analyzed from the iFR-pullback study. The mean length of the stent implanted was 43 ± 9 mm and the reduction of stent length was 12 ± 8 mm on the angiographic analysis. With these data, we have stablished an expected length reduction of 15 mm. The calculated sample size to achieve the primary endpoint with an 80% confidence level and a 5% margin of error was 100 patients.

RESULTS

The recruitment of patients started back in February 2020. After 1 month, we have included the first 7 patients. We expect to complete the recruitment by February 2021 and the follow-up by February 2022.

DISCUSSION

To our knowledge, this randomized study is, the first one to assess the potential benefits of using the SyncVision software in long, sequential or diffuse coronary lesions. Currently, the study is in the recruitment phase and the first patients have already been recruited.

The iFR has proven to be useful in the PCI guide decision-making process.7,8 However, the evidence supporting the use of SyncVision is scarce and controversial in long, sequential or diffuse lesions. On the one hand, the software allows us to know the coronary segments with the highest physiological compromise. This allows us to revascularize only those segments that immediately improve the physiological result with a potential reduction of the length of the stent implanted, which happens to be a predictor of MACE at the follow-up.9 On the other hand, it’s possible that even if we obtain a good immediate physiological result and a reduction of the stent length implanted we won’t be fully covering the plaque in some lesions or coronary segments, which has also proven to be a predictor of MACE.6

A limitation of the study is the sample size, enough to achieve the primary endpoint, but probably inadequate to see differences in MACE. However, we think that it can provide an early insight on the utility of iFR pullback study to guide the PCI decision-making process in this type of lesion. Also, it can be a hypothesis-generator study for future larger-scale studies to show benefits in terms of clinical events reduction.

For these reasons, we believe that the iLARDI is an interesting study that will shows us the potential benefit of SyncVision to guide the PCI decision-making process in long, sequential or diffuse coronary lesions. We intend to complete the results by February 2022.

CONCLUSIONS

The iLARDI study is the first randomized trial to assess the potential utility of SyncVision-guided revascularization in long, sequential and diffuse coronary lesions.

FUNDING

Funds from the Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI) have been used to pay for the liability insurance associated with clinical research.

AUTHORS' CONTRIBUTION

All the authors have participated in the study and in the manuscript:

F. Hidalgo has participated has mainly drafted of the manuscript and has participated in the conception and design of the study. R. González has also participated in the conception and design of the study, and in the analysis and interpretation of data. S. Ojeda has mainly participated in the conception, design of the study and revision of the manuscript. C. Pericet has participated in the conception and design of the study. A. Lostalo has also collaborated in the analysis and interpretation of data. J. Segura has also revised it critically for important intellectual content. N. Paredes and J.C. Elizalde have also contributed in the analysis and interpretation of data. A. Luque has participated in the draft of the manuscript. F. Mazuelos has also contributed in the analysis and interpretation of data. J. Suárez de Lezo and M. Romero have revised it critically for important intellectual content. M. Pan has done the final approval of the manuscript submitted.

CONFLICTS OF INTEREST

F. Hidalgo, S. Ojeda, and J. Segura received personal fees from Philips Volcano. M. Pan received minor fees from Abbott, Philips Volcano, and Terumo. The remaining authors declared no conflicts of interest whatsoever.

 

 

REFERENCES

INTRODUCTION

Over the last few years, the profile of patients referred to undergo a coronary angiography has become worse. Similarly, angiographic findings have become worse as well. Recently, De María et al.1 published a study on the management of calcified lesions. They provided a nice contemporary overview on the management of calcified lesions in the catheterization laboratory focusing on the technologies available, intravascular imaging, and technical complexities. However, an important marker of procedural complexity was omitted: coronary bifurcation lesions. CBLs are often seen in interventional practice and can be challenging in our routine clinical practice. Yet spite the existence of several well-defined techniques to perform a percutaneous coronary intervention (PCI) on a CBL, side-branch compromise is still the most important problem.2^,3 Currently, the standard strategy (SS) recommended for the management of CBL is a 1-stent technique2^,4 (balloon angioplasty and provisional stenting) since it has proven to be non-inferior to the elective 2-stent technique.5 It is well-known that rotational atherectomy (RA) is underused during the PCI6 and no specific randomized data are available regarding its role in the management of CBL. The role of RA in this setting has been suggested in different studies not designed for that purpose. Data published reveal that in up to 26% of the cases the indication for RA was to preserve the side-branch.7^-9 As far as we know, this extended use of RA is an off-label indication that has not been specifically tested in a randomized study. We report the procedural and long-term results of the rotational atherectomy and provisional stenting (RAPS) strategy compared to the SS (balloon angioplasty and provisional stenting) in a randomized pilot study.

METHODS

Study population

We conducted a single center, prospective, randomized pilot study of consecutive patients from our center with bifurcation lesions located only in main vessel (BLMV) and who were screened before being recruited. The angiographic criteria to define the CBLs that were eligible for the study were: a) lesions: > 70% located in a major bifurcation point regardless of the length, morphology, and angulation of the bifurcation lesion; b) thrombolysis in myocardial infarction (TIMI) flow grade > 2 on both the main vessel (MV) and the side-branch (SB); c) MV visual diameter: ≥ 2.5 mm; and 4.0. SB visual diameter: ≥ 2.0 mm. The presence of a heavily calcified lesion was not a prerequisite to enter the study.

The inclusion criteria were patients ≥ 18 years who signed their informed consent with Medina lesions type 1.0.0; 1.1.0 and 0.1.0 and who were eligible to undergo either one of the 2 strategies and with no confirmed or suspected contraindications for prolonged dual antiplatelet therapy.

The exclusion criteria were: a) SB < 2 mm; b) lesions with thrombus or dissection; c) vein graft lesions; d) cases of a single main vessel with severe left ventricle dysfunction (EF < 30%); e) hemodynamically unstable patients; f) contraindication for prolonged dual antiplatelet treatment; g) life expectancy < 1 year; and h) patient refusal.

Procedures

The random assignment of patients to the different treatment groups was done using the EPIDAT 4.0 software. After obtaining the patients’ informed consent they were randomized in a 1:1 ratio to the RAPS group, RA group or SS group. Patients were revascularized according to the current recommendations.1^,10 In the SS group the strategy used was left to the operator’s discretion: 1 or 2 wires, previous BA or direct stenting, 1- or 2-stent technique, etc. Everything was decided in each case by the operator. In the RAPS group a single RotaWire was used in the main vessel and only in this vessel rotational atherectomy would be performed (videos 1-7 of the supplementary data).

The baseline clinical data collected include demographics and the patients’ cardiovascular past medical history and comorbid conditions. Both the angiographic and PCI data were recorded. The RA technique was performed following the current recommendations.6 CBLs were classified according to their angles: < 70º or ≥ 70º. Two different operators assessed each individual case.

Endpoints

The primary endpoint was defined as “need for side-branch therapy”. This “need for side-branch therapy” was considered in the presence of clinical, ECG or hemodynamic signs suggestive of TIMI flow ≤ 2 and/or ostial stenosis ≥ 70%.11 In contrast, “side-branch compromise” was considered when in the presence of impaired SB stenosis or TIMI flow whether severe or not. The secondary endpoints were: a) Target vessel failure (TVF): a composite of cardiac death, culprit vessel myocardial infarction, target vessel restenosis, and target bifurcation restenosis at the follow-up (appendix of the supplementary data); b) Angiographic outcomes: B.1. Procedural and annual assessment success rate and its correlation with the bifurcation angle. Procedural success was defined as TIMI flow grade-3 in both the MV and the SB and a visual residual stenosis < 20% in the MV; B.2. Angiographic complications rate including stent thrombosis, dissection, occlusion, perforation, no-reflow, target lesion restenosis (TLR), and target bifurcation restenosis at the FUP. c) The major adverse cardiovascular and cerebrovascular events (MACCE). Other relevant conditions such as hemorrhages, need for transfusion, and kidney disease were also recorded. All deaths were considered cardiac unless a definite non-cardiac cause was established. Both the bifurcation technique and stent used were left to the operator’s discretion.

The periprocedural drugs and laboratory test definitions are shown on in the appendix of the supplementary data. After discharge, the patients’ clinical follow-up was conducted through personal interviews or phone calls every 6 months. Patients underwent angiographic control clinically driven only. The monitoring of cardiovascular risk factors, drugs compliance, and blood test controls were left to the discretion of the referring physician.

The aforementioned study has been conducted in full compliance with The Code of Ethics of the World Medical Association Declaration of Helsinki. Also, it has been approved by the hospital local ethics committee. The patients’ written informed consent was obtained too.

Sample size

No randomized studies on this subset are available so we could not use the sample size formula. Instead, we used the ARCSIN approximation function and estimated that, at least, 60 subjects should be included in each group to find statistically significant differences (accepting an alpha risk of 0.05 and a beta risk of 0.2 in two-sided tests). A drop-out rate < 1% was anticipated.

Statistical analysis

Data were expressed as means ± standard deviation (SD) for the continuous variables and as frequencies and percentages for the categorical ones. The FUP period was expressed as the median with its interquartile range [IQR]. The chi-square or Fisher’s exact tests that assessed the effect and accuracy analyses with the prevalence ratio and 95% confidence interval, when necessary, were used to compare the continuous and categorical variables, respectively. The Mann-Whitney test was used to study the non-parametric variables. Cox regression models were used to perform univariate analyses to estimate the associated hazard-ratio of death and composite endpoints at the FUP. A multivariate analysis was performed as well. The Kaplan-Meier estimates were used to determine the time-to-event outcomes, overall survival rate, and MACCE-free survival rate. We tested the equality of the estimated survival curves using the stratified log-rank test. All analyses were performed using the Statistical Package for Social Scientists (SPSS Inc., 20.0 for Windows). P values < .05 were considered statistically significant in all of the tests.

RESULTS

One-hundred and seventy-three out of 1028 patients who underwent a PCI between January 2015 and December 2018 were considered eligible to enter the study: 13 refused to participate, 8 patients dropped-out, and 4 patients withdrew their informed consent. Finally, 148 patients were included: 74 patients (95 RAs) were recruited in the RAPS group and 74 patients in the SS group. The inclusion/exclusion flowchart is shown on figure 1 of the supplementary data.

The baseline clinical, angiographic, and procedural data are shown on table 1 and table 2. No sex-based differences were seen. Only the prevalence of a left ventricular ejection fraction ≤ 45% was different between the groups: P = .03. No calcification, tortuosity or bifurcation angle differences were reported. The most common bifurcation was found at the first diagonal branch of the proximal left anterior descending coronary artery (D1-LAD) (51%) followed by the distal left main coronary artery (LMCA)/ostial LAD (22.5%) No inter-group differences in single vs staged revascularization were seen.

Table 1. Baseline characteristics

Baseline clinical data	RAPS (N = 74)	SS (N = 74)	P
Age (mean; SD)	78 (10)	74 (7)	NS
Males (n; %)	60 (81.2)	58 (78.1)	NS
Weight (mean; SD)	73.9 (11.9)	75.4 (11.4)	NS
Height (m) (mean; SD)	1.64 (0.7)	1.66 (0.6)	NS
Body mass index (mean; SD)	27.11 (3.4)	29.24 (11.4)	NS
Current/Previous smoker (n; %)	46 (62.1)	53 (71.6)	NS
Hypertension (n; %)	62 (92.2)	74 (100)	NS
Diabetes mellitus (n; %)	29 (39.1)	30 (40.6)	NS
Dyslipidemia (n; %)	69 (93.2)	62 (83.7)	NS
Left ventricle ejection fraction ≤ 45 (%)	28 (37.8)	14 (18.7)	.03
Previous myocardial infarction (n; %)	42 (56.7)	37 (50)	NS
Previous angioplasty	42 (56.7)	32 (43.2)	NS
Previous Stroke (n; %)	10 (14.1)	18 (24.3)	NS
Peripheral vascular disease (n; %)	16 (21.6)	23 (31)	NS
L-Euroscore (mean; DS)	21.14 (22.15)	13.7 (18.7)	NS
Syntax Score (mean; DS)	34.05 (17.9)	31.57 (17.9)	NS
Clinical onset (n; %)
Stable angina	14 (19)	20 (27)	NS
NSTEMI	40 (54)	47 (63.5)	NS
STEMI	20 (27)	7 (9.4)	NS
Discarded for cardiac surgery (n; %)	24 (32.4)	20 (27)	NS
NYHA Class ≥ III	8 (9.3)	9 (12.1)	NS
CCS I-II	57 (77)	41 (55.4)	NS
CCS III-IV	17 (23)	32 (44.6)	NS
CCS, Canadian Class Classification angina score; NS, not significant; NSTEMI, non-ST-elevation acute myocardial infarction; NYHA: New York Heart Association; RAPS, rotational atherectomy and provisional stenting; SS, standard strategy; SD, standard deviation; STEMI, ST-segment elevation myocardial infarction.

Table 2. Angiographic and procedural data

Angiographic/procedural data	RAPS (N = 74)	SS (N = 74)	P
6-Fr sheath (n; %)	62 (88)	60 (81.2)	NS
Radial Approach (n; %)	29 (39.1)	30 (40.6)
Femoral approach (n; %)	45 (60.9)	44 (59.3)
Coadjuvant therapy (n; %)
Heparin	21 (28.1)	29 (40.6)	NS
Bivaluridin	42 (56.3)	23 (31.2)	.01
Glycoprotein inhibitors	11 (15.9)	23 (31.2)	NS
Right Dominance (n; %)	64 (87.5)	64 (87.5)	NS
Vessel disease (n; %)
Left Main coronary artery	15 (20.3)	14 (18.7)	NS
Left anterior descending coronary artery	72 (98.4)	57 (78.1)	.02
Left circumflex artery	47 (64.1)	55 (71.8)	NS
Right coronary artery	54 (73.4)	57 (78.1)	NS
Number of diseased vessels (n; %)
1 vessel	10 (13.5)	13 (17.53)	NS
2 vessels	22 (29.7)	24 (32.4)	NS
3 vessels	34 (45.9)	31 (41.8)	NS
4 vessels	8 (10.8)	6 (8.1)	NS
Multivessel (n; %)	60 (81.2)	53 (71.8)	NS
Coronary calcification (%)
Mild	28	36	NS
Moderate-severe	72	64	NS
B2C lesions (n; %)	94 (98.4)	60 (81.2)	.048
Medina classification of bifurcation lesions (n; %)
1.0.0	46 (48.4)	17 (23)	.04
1.1.0	32 (33.6)	22 (29.7)	NS
0.1.0	17 (17.8)	30 (40.1)	.03
Bifurcation angle (n; %)
< 70º	46 (62)	50 (67.5)	NS
≥ 70º	28 (38)	24 (32.5)	NS
Wire
Floppy [n (%)]	88 (92.4)	N/A	NS
Directly advanced [n (%)]	84 (88.5)	N/A	NS
Burr size ≤ 1.5 mm	76 (80)	N/A	NS
Speed (rpm) (mean; SD)	134650 (5670)	N/A	NS
Rotational atherectomies performed (% per patient)	95 (1.28)	N/A	NS
Burr-to-artery ratio (mean; SD)	0.55 (.04)	N/A
Number of balloons per lesion	1.3	4.6	.02
Stent (n)
Number of stents per lesion	1.6	2.3	.04
Number of stents per patient	2.7	2.33	NS
Bare-metal stent [n (%)]	24 (12.7)	22 (23.2)	NS
Drug-eluting stent [n (%)]	167 (86.9)	72 (76.7)	NS
Stenting technique [n (%)]
Provisional stenting	64 (100)	41 (55.4)	.04
Two-stent initial approach technique	0	28 (37.8)	< .001
Optimal treatment of the proximal LAD	48 (64.8)	24 (32.4)	< .05
Final kissing balloon technique	1 (1.5)	59 (79.7)	< .001
Final inflation pressure (atm)	18	14	.05
Initial vessel diameter (Me; IQR) (mm)	2.41 (0.34)	2.89 (0.26)	.009
Final vessel diameter (Me, IQR) (mm)	3.1 (1.9)	2.95 (0.37)	NS
Maximum length stented (Me; IQR) (mm)	56 (48)	44 (26.1)	.005
Procedural time (min) (mean; SD)	78.8 (30)	98 (21)	.04
Fluoroscopy time (min) (mean; SD)	13 (7)	29.2 (21)	.02
Contrast media (ml) (mean; SD)	179 (74)	221 (73)	.05
IVUS/OCT	7 (9.4)	11 (14.8)	NS
IVUS, intravascular ultrasound; Me, median; NS, not significant; NYHA, New York Heart Association; OCT, optical coherence tomography; SD, standard deviation.s

Long-term follow-up

Both the clinical and angiographic success rates and outcomes were available for the entire population with a median FUP of 4.08 years [IQR: 3.18-4.78 years]. Both the all-cause and cardiovascular mortality rates were similar in both groups. The need for side-branch therapy was consistently lower in the RAPS strategy compared to the SS: 1.1% vs 27% (P < .001) (table 3). TVF was 12.1% and 24.8% (P =.04) in the RAPS strategy compared to the SS, respectively. Also, the statistical analysis confirmed that the use of the RA technique significantly reduced the risk of target vessel restenosis (P = .04), TLR (0.02), target bifurcation restenosis (P = .03), and major adverse cardiovascular events (P = .03). A positive correlation (r = 0.673, P = .03) was seen between the need for SB therapy and CBL angles < 70º. The strongest correlation was observed at the proximal D1-LAD: r = 0.79, P = .03. A weak but positive correlation was seen between the LMCA-LAD arteries angle (r = 0.412, P = .04) and the LMCA-LCx arteries angle (r = 0.342, P = .004). The sum of SS plus CBL angles < 70º was associated with a higher risk of SB compromise and TVF (OR, 4.92; 95%CI, 1.78-14.1; P = .03)

Table 3. Major adverse cardiovascular events at the follow-up

	RAPS (N = 74)	SS (N = 74)	P
Clinical success (%)	98.6	98	NS
Associated cardiovascular mortality (hospitalizations) [n (%)]	3 (4)	2 (2.7)	NS
With procedure	2 (2.7)	2 (2.7)
With rotational atherectomy	1 (1.3)	N/A
Angiographic success (%)	96.5	97.5	NS
Angiographic complications [n (%)]
Unable to advance the wire	1 (1.3)	2 (2.7)	NS
Burr entrapment	0	N/A	NS
Unable to deliver the stent	1 (1.3)	2 (2.7)	NS
Coronary dissection	1 (1.3)	6 (8,1)	.024
Side-branch compromise*	2 (2.7)	23 (31)	< .001
Need for side-branch therapy**	1 (1.3)	20 (27)	< .001
Perforation	0	0	NS
Cardiac tamponade	0	0	NS
Stent thrombosis	0	0	NS
Need for pacemaker implantation	0	0	NS
Final flow compromise (TIMI ≤ 2) in SB	0	2 (2.7)	NS
MACCE (4.08 years, ICA: 3.18-4.78)
GLOBAL: 27 (36.4%)	18 (25%)	30 (40.6%)	.03
Overall death rate	15 (20.3%)	16 (21.8%)	NS
Hospitalization	3 (4%)	3 (4%)	NS
30 days	4 (5.4%)	5 (6.7%)	NS
Cardiac Death	5 (6.7%)	7 (9.4%)	NS
Non-cardiac Death	9 (12.1%)	7 (9.4%)	NS
Stroke	2 (2.7%)	7 (9.4%)	.02
TVF	9 (12.1%)	18 (24.8 %)	.04
TLR	2 (2.7%)	11 (14.8%)	.02
TVR	3 (4%)	7 (9.4%)	.03
TBR	2 (2.7%)	7 (9.4%)	.03
Stent thrombosis	0	0	NS
ICA, interquartile amplitude; MACCE, major adverse cardiovascular and cerebrovascular events; NS, not significant; RAPS, rotational atherectomy and provisional stenting; SS, standard strategy; TBR, target bifurcation restenosis; TLR, target lesion restenosis; TVF, target vessel failure (composite of cardiac death, culprit vessel myocardial infarction); TVR, target vessel restenosis. * Shift plaque defined as ostial side-branch stenosis > 70% and/or TIMI flow < 3. ** Treatment included: a) angioplasty with conventional or drug-eluting balloon; b) bare-metal stent or drug-eluting stent.

DISCUSSION

Main findings

The main findings of this study are: a) the RAPS strategy for the management for CBLs minimizes the compromise of the SB, need for SB therapy, and TVF compared to the SS; b) There was a strong correlation between the compromise of the SB and acute CBL angles (< 70º); c) The SS was associated with a 4.92-fold higher risk of SB compromise compared to the RAPS strategy in CBL angles < 70º.

CBLs are a common thing in our interventional practice and can be challenging in our routine clinical practice. Side-branch compromise is still the most important problem. To our knowledge, this is the first randomized study that addressed this issue and described the role of RA in the management of CBLs. Former studies not specifically designed to address this specific question had already suggested this.8^,9^,12^,13 We reported sustained short-term benefits of the RAPS strategy at the long-term follow up. Some differences had been previously reported,14 which is why differences in the primary endpoint could be expected, but still not so significant.

As a hypothesis-generating pilot study we defined a procedural primary endpoint.11 Selecting a “procedural” primary endpoint at this stage is a reasonable thing to do since the occlusion of large SBs is a serious complication that leads to adverse clinical outcomes.11^,14 We studied whether the RAPS strategy could be as good as the SS for the management of CBL by comparing the compromise of the SB.15^-17 Still, the current clinical practice guidelines minimize the indications for RA to heavily calcified lesions and rigid ostial lesions,10 although an expert consensus document recently published includes more extensive indications.6 The real-world use of RA for plaque modification in is nothing new.9 Actually, in the absence of plaque modification there are more chances of procedural failure, stent underexpansion, in-stent restenosis, and major clinical complications.2^,5^,18 Schwartz et al use it in up to 26% of their population.9

Percutaneous coronary intervention and bifurcation technique

Only BLMVs were included.19 Bifurcations are true bifurcations when a significant SB runs the risk of being compromised regardless of whether the disease reaches it or not. Thus, maybe we should rename them as “complex CBLs”, that is, those where the SB has baseline disease (1.1.1 in the Medina classification) and “simple CBLs”, those without baseline disease (again according to the Medina score). There is wide consensus that the main objective of complex PCIs in the management of CBLs is to keep the patency of both vessels regardless of the PCI technique used and the location of the lesion.2 For many years we have been focused on the optimization of SB, but clinical events such as TLR mostly occur in the main vessel.20 In up to 20% of the cases, the SB requires a stent, which means that the proper preparation of the CBL is essential.3^,14^,21

What the best bifurcation technique is for the management of CBL is still under discussion. Currently, the standard strategy recommended for the management of CBL is a 1-stent technique.2^,4 Ideally, the technique selected should provide an easy access for a second stent in the SB even if conventional approach with a 1-stent technique is planned. In our cohort, the RA facilitated this approach. According to cumulative clinical trial data3 we reported a high rate of provisional stenting in the RAPS strategy that proved non-inferior to the elective 2-stent technique4^,5 and ever better for the management of periprocedural myocardial infarction.22 The kissing balloon technique is being systematically used in cases of large territories supplied by the SB or when the SB exhibits flow impairment after MV stenting. Sometimes, in such situations a second stent is implanted in the SB.23 The differences reported in our population regarding the optimal treatment of the proximal LAD and final kissing balloon and 2-stent technique used are still under discussion. We saw a 4-fold higher rate of the balloon technique in the SS. Maybe these differences were due to the tight lesions described: in the SS there was a need of a step-up ballooning to cross and dilate the lesions and eventually for the final optimization of the stents. Eventually, at least 3 or 4 balloons were needed. Interestingly, as previously reported, when the final kissing balloon technique was used, the optimal treatment of the proximal LAD produced no benefit at all.24 Maybe this was the case because the stent located in the main vessel is properly expanded after using the kissing balloon technique. We saw a lower need for SB treatment and TVF rates7^,18^,25 in the RAPS strategy than previously reported.

Role of rotational atherectomy for the management of bifurcation lesions

The RAPS strategy facilitates the modification of the plaque without SB compromise by extending provisional stenting2^,4 by a) minimizing plaque shift, b) optimizing plaque modification, c) reducing the need for 2 wires/stents and d) improving the stent expansion/apposition. Otherwise, certain maneuvers used in other strategies to avoid the occlusion of the SB may cause suboptimal stent expansion/apposition in the MV, which can be a major cause for stent thrombosis and restenosis.2^,14 The bifurcation angle has been suggested as an important issue for the compromise of the SB.5^,11^,14 In our population, the LAD was the most commonly affected coronary artery. The LAD is particularly appealing given the angle of the origin of the diagonals. The crux is often at a right angle so it is less of a concern and the circumflex artery only matters when it is dominant. Acute CBL angles (< 70º) have shown to increase the compromise of the SB and, therefore, lead to worse outcomes. In our cohort, “SB compromise”, “need for SB therapy”, and TVF rates were lower in CBL angles < 70º both in the RAPS and the SS groups. The small size of the sample prevented us from drawing definitive conclusions, but these data were good enough to make us change our daily methodology: with CBL angles < 70º located in the main vessel with a large side-branch we use directly the RAPS technique. Maybe the explanation for the differences seen in the RAPS vs the standard strategy is the underlying mechanism of action of rotational atherectomy. As a matter of fact, this may explain the higher rates of SB compromise and need for SB therapy seen in the SS group: a more controlled plaque modification was achieved with RA that minimized the plaque shift. Unfortunately, our data did not include too many imaging modalities. In our cohort for events assignment, if during the PCI procedure any narrowing occurred adjacent to, and/or involving the origin of a significant SB it was allocated to the selected strategy used. The decision to use the 1-stent or 2-stent technique, the type of stent, etc. was left to the operator’s discretion. We should make a few comments on our study population: a) although most of the patients were unstable, this did not condition the results in any of the groups; b) in the RAPS strategy the use of the jailed wired technique is rare; c) CBL angles < 70º between branches facilitate the plaque shift.26 Thus, if the TIMI flow recorded after stent deployment was < 3 or residual stenosis was > 70% more bail-out balloons and stents were needed, which would explain the different outcomes seen when using the final kissing balloon technique; d) in a number of cases where the standard strategy was used it was complemented with the kissing balloon inflation technique at high-pressure balloon inflation instead of the final optimal treatment of the proximal LAD; and e) the differences seen in the coronary dissection rate on the angiographic study may be suggestive of micro-dissections due to inadequate balloon assessment through conventional angiography, which could be the underlying mechanism of the endpoint differences reported; performing more intravascular ultrasound/optical coherence tomography studies would provide better assessment here.

Patients were randomized in a 1:1 ratio so the differences seen in the left ventricular ejection fraction and LAD disease were absolutely due to the size of the study sample. Although we saw a lower cardiovascular mortality rate compared to the one published in the medical literature2^,14^,15^,27 this study was not designed to compare the MACCE results between both groups. Interestingly, the rates of TVF were significantly lower in the RAPS strategy mainly due to fewer culprit vessel myocardial infarctions and target vessel restenoses. In any case, our data underscored the safety profile of the RAPS strategy in unstable patients and patients with left ventricular dysfunction (P = .03)

Limitations

We designed and conducted a single-center pilot study. Small sample sizes have inherent limitations. Our results should be interpreted with caution as a hypothesis-generating pilot study. Several confounding factors and biases could be present, which is why any assessments on this regard should be made with caution too. The study was extremely underpowered to show clinical outcome differences, which is why the clinical findings reported should be considered just exploratory. Our procedural endpoint and inclusion of BLMVs only could be discussed. There is wide consensus that the main objective of complex PCsI for the management of CBLs is to keep both vessels patent regardless of the PCI technique used.2

We thought it was the right thing to do to assess the data on the SB compromise by comparing both techniques used. Over thec years we have been focusing on optimizing the SB, but clinical events such as TLR mostly occur in the main vessel.20 Only BLMVs were included.19 A bifurcation should be considered as a true bifurcation when a significant SB you do not want to lose is compromised whether it shows coronary stenosis or not. We should mention that in the management of CBLs with the RAPS strategy a low rate of SB stenting is associated with a lower rate of major adverse events and clinically significant rates of restenosis. Therefore, very large numbers of patients are required for the proper assessment of the differences. Some baseline characteristics of coronary lesions vary depending on the interventional strategy used (as in the management of B2C lesions) to the point of impacting the final outcomes. The lack of differences seen in the stent thrombosis and stroke rates may be associated with the size of the study sample.

Although statistical significance was not observed, the percentage of bare metal stents used was numerically higher in the control group compared to the RAPS group. However, this study is not a comparison of drug-eluting stents versus bare-metal stents in bifurcation disease. These findings could be associated with the difference seen in TLR/target vessel restenosis, especially if we take into account that 31.2% of patients from the control group were treated using 2-stent techniques. We saw that RA followed by drug-eluting stents was associated with a low rate of MACCE compared to bare-metal stents. However, this study was not designed to make comparisons like this one. A higher percentage of bivaluridin was intentionally used in the RAPS group, but this did not produce any statistically significant differences. The use of more imaging modalities such as intravascular ultrasound or optical coherence tomography is desirable here. FUP was mostly conducted through phone calls and it may have underestimated the rate of MACCE. An off-label indication does not necessarily mean a contraindication of our promising, but support for the next step: a large randomized multicenter trial that is about to begin.

CONCLUSIONS

The RAPS strategy for the management of CBL preserves the SB ostium and minimizes the need for SB therapy compared to the SS. The rates of “SB compromise”, “need for SB therapy”, and TVF were higher with CBL angles < 70º for both the RAPS and the SS groups. Our data reinforce the idea of the overall clinical relevance of the RAPS strategy to keep the SB patent. Although no large clinical trials have taken this approach yet, the results published so far are promising.

CONFLICTS OF INTEREST

J. Palazuelos (corresponding author) is a consultant on the speaker’s bureau of Abbott, Boston Scientific, Biotronik, Innovative Health Technologies (IHT) and Medtronic. J. Palazuelos is a proctor for Rotational Atherectomy with a teaching contract with Boston Scientific that has funded this study with a grant. No other relation with the industry regarding this study was declared. He confirms he has had full access to all the study data and holds full responsibility for the decision to submit this manuscript for publication in Rec: Interventional Cardiology. The remaining authors have declared no conflicts of interest whatsoever regarding the contents of this manuscript.

 

 

REFERENCES

INTRODUCTION

Renal function impairment is associated with poor prognosis in patients with stable or acute coronary syndrome (ACS). One of the most common causes of acute kidney injury (AKI) in hospitalized patients is the nephropathy induced by the IV administration of contrast agents.1Its incidence varies between 1% and 6%, and increases considerably in high-risk conditions like in the ACS setting. The reported frequency of post-coronary angiography contrast-induced nephropathy (CIN) goes from 12% to 46% in patients with ACS.2^,3

There are several potential causes that trigger CIN in patients without a past medical history of kidney failure such as hemodynamic instability, the IV administration of contrast agents, thromboembolic events, and adverse drug reactions, among others. Also, it is important to consider the type of contrast used, its osmolarity, the volume administered, and the lack of preventive measures.4^-6

Because CIN is associated with poor prognosis in hospitalized patients, predictive scores have been designed to identify the most vulnerable patients who can develop this complication. The Mehran score is one of the most popular indices to estimate the chances of post-coronary angiography CIN.7

It is well-established that microalbuminuria is a predictor of kidney dysfunction mainly in diabetic and hypertensive patients.8^-14Also, there is a correlation between high levels of microalbuminuria and the poor outcomes seen in patients with ACS.15^-16 Currently, microalbuminuria is estimated through the dosage of the albumin-to-creatinine ratio (ACR) through a simple urine sample.17

The objective of this study is to calculate microalbuminuria using the ACR as a predictive variable of post-coronary angiography CIN in patients with ACS.

METHODS

Population

Patients with ACS consecutively admitted to the coronary care unit of a community hospital were analyzed. Those undergoing an in-hospital coronary angiography with non-ionic, hyperosmolar IV contrast agents such as iopamidol, optiray or xenetix, were included in the study. The volume of IV contrast for each angiographic study was calculated retrospectively. It was estimated that each injection of contrast material into the left coronary artery required an average 10 cc to 8 cc for the right coronary artery.

Patients with a past medical history of renal failure, macroalbuminuria, treatment with diuretics and patients with secondary angina were excluded from the study.

The urinary ACR was assessed in all patients included in the study using an immunoturbidimetric assay in simple urine samples within the first 24 hours after hospitalization.

Definitions

IV contrast-induced nephropathy(CIN) was defined as an increase in serum creatinine levels ≥ 25% 48 hours after performing the coronary angiography or an absolute increase of ≥ 0.5 mg/dL compared to levels at admission.

Microalbuminuria was defined as an abnormal urinary albumin excretion rate between 30 to 200 mg/min or 30 to 229 mg/day.

The study protocol was approved by the center review board and conducted in compliance with the Declaration of Helsinki, good clinical practice guidelines, and local regulatory requirements. Informed consents were obtained from all patients.

Biochemical considerations

A urine sample collected within the first 24 hours after admission (preferably during morning hours) was centrifuged at 3000 rpm and stored at -20° Celsius until biochemical analysis was conducted. The principle of the ACR test is immunoturbidimetry. This method is based on the reaction of human albumin antibodies to the antigen. Complexes are then measured after agglutination. The COBAS 6000 analyzer (ROCHE, Switzerland) was used to process the sample. The analytical detection limits of the assay were between 3 mg/g and 400 mg/g. The test variation coefficient was 3.8%.

Statistical analysis

The Kolmogorov-Smirnov test was used to analyze the distribution of continuous variables and their kurtosis-skewness measures. Data were expressed as mean and standard deviation or as median with interquartile range (25%-75%) and compared using Student’s t test or Mann-Whitney-Wilcoxon test for independent groups according to their parametric or non-parametric distribution, respectively.

Discrete variables were expressed as percentages and compared using the chi-square test. The cross-product ratio was expressed as odds ratio (OR) with its 95% confidence interval (95%CI). The C-statistic measure was used to detect the best ACR cutoff value associated with the primary endpoint and compare the discrimination capacity of the Mehran score alone and with the ACR combined.

A multivariable regression analysis will be built to predict CIN including ACR and adjusted using the Mehran score.

Both the IBM SPSS Statistics version 19 software and the MedCalc version 11.6.1 software (Mariakerke, Belgium) were used for statistical analysis and to calculate and compare the C-statistic measure. To test the additional predictive value of ACR, the C-statistic measurewas compared using the Mehran score alone and after adding the ACR information obtained.

RESULTS

Out of a total of 397 patients diagnosed with ACS, 148 (59.4%) underwent a coronary angiography during hospitalization and this was the study population. The mean age was 64 ± 12 years; 35% were women, 20% had diabetes, 54% dyslipidemia, 65% hypertension, and 42% were active smokers. The mean blood sugar levels on admission were 110 mg/dL (98-133 mg/dL), the median creatinine clearance rate (estimated using the MDRD) was 86 mL/min (66-107), and the ACR was 5 mg/g (0-14) (table 1). The patient comparison between these groups with or without CIN showed a higher rate of overweight and obesity, left bundle branch block, atrial fibrillation, and AMI Killip and Kimball class III-IV (table 2).

Table 1. Baseline characteristics of the patients

Total number of patients	N = 148
Age (years), median [25-75]	64 [56-73]
Women	35
Hypertension	65
Diabetes mellitus	20
Dyslipidemia	54
Smoking	42
Previous AMI	24.5
STEAMI	20.9
NSTEACS	79.1
Fasting blood glucose levels, mg/dL	110 [98-133]
Serum creatinine levels, mg/dL	0.9 [0.8-1.0]
Creatinine clearance rate, mL/min	86 [66-107]
Urinary albumin-to-creatinine ratio, mg/gr	5 [0-14]
CPK, IU/L	121 [73-264]
CK-MB, IU/L	16 [12-34]
Troponin T levels, ng/mL	0.01 [0.01-0.27]
Moderate to severe LVSF impairment (EF < 40%)	5.79
Unless specified otherwise, data are expressed as % or mean and standard deviation. AMI, acute myocardial infarction; CK-MB, creatine kinase myocardial band; CPK, creatine phosphokinase; EF, ejection fraction; IQR, interquartile range; IU, international units; LVSF, left ventricular shortening fraction; NSTEACS, non-ST-segment elevation acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction.

Table 2. Comparison of patients with and without contrast-induced nephropathy

	CIN - (136)	CIN + (12)	P
Age (years)	63.7 [55-74]	68 [61-76]	NS
Women	25.3	16.7	NS
Hypertensive	67.7	58.3	NS
Diabetic	20	33.3	NS
Body mass index	26 [24-29]	29 [25-31]	.05
Creatinineclearence rate mg/dL	85 [65-108]	74 [50-98]	NS
Blood glucose levels at admission, mg/dL	112 [100-142]	143 [108-209]	NS
Previous AMI	26	16	NS
Previous PCI	17	8.3	NS
Previous stroke or TIA	3.6	8.3	NS
NSTEACS	17.7	25	NS
STEMI	30.8	33.3	NS
Left bundle branch block	3.6	16.7	.02
Atrial fibrillation	0.9	8.3	.02
Killip and Kimball III-IV	4.1	22	.001
Unless specified otherwise, data are expressed as % or mean and standard deviation 25%-75%. ACEI, angiotensin-converting enzyme inhibitors; AMI, acute myocardial infarction; ARA II, angiotensin II receptor antagonists; ASA, acetylsalicylic acid; CK-MB, creatine kinase myocardial band; CPK, creatine phosphokinase; EF, ejection fraction; HR, heart rate; IQR, interquartile range; IU, international units; LVSF, left ventricular shortening fraction; NS, not significant; NSTEACS, non-ST-segment elevation acute coronary syndrome; PCI, percutaneous coronary intervention; SBP, systolic blood pressure; STEMI, ST-segment elevation myocardial infarction; TIA, transient ischemic attack.

The C-statistic measure showed that the best CIN related ACR cutoff value was 20 mg/g. Twelve patients developed CIN (8.1%) and the ACR of 22% of the patients was >20 mg/g. The rate of ACR > 20 mg/g among patients without CIN was 2.9% and 11.3% (P = .01) among patients with CIN. Contrast-induced nephropathy was significantly higher when the ACR was ≥ 20 mg/g compared to when it was < 20 mg/g (≥ 9.6% vs 1.6%, res­- pectively, P < .001). When the ACR was added to the Mehran score, its predictive power went up to 0.82 (95%CI, 0.76-0.87).(Figure 1).

Figure 1. Effect of albumin-to-creatinine ratio when added to the Mehran score. When the albumin-to-creatinine ratio was added to the Mehran score, its predictive power went up from 0.75 to 0.82 (95%CI, 0.76-0.87).

Using a multivariable regression analysis model the ACR > 20 mg/g turned out to be an independent predictor for CIN: OR, 3.2 (0.7-6.2); P = .01, adjusted by the Mehran score variables (age, women, body mass index, atrial fibrillation, Killip Class III-IV, and creatinine clearance rate).

DISCUSSION

Our study proved the association between the ACR and the development of CIN in patients admitted with ACS.

Acute kidney injury in the ACS setting predisposes to more complications such as in-hospital and long-term mortality; therefore, predicting it is of critical clinical importance. A recent study reported that the rate of AKI was close to 17% in the ACS setting with significant peaks of cardiovascular complications. In this study, the ACR was not used as an early marker of AKI. The development of CIN was not specifically analyzed either as a post-coronary angiography compli­cation.18^-22

Microalbuminuria calculated through the ACR obtained from a simple urine sample is also an established marker of endothelial dysfunction that has been validated to predict cardiovascular events and mortality in different clinical settings. A previous analysis of our group revealed that higher ACR levels are associated with significantly worse outcomes in patients with non-ST-segment elevation ACS, and with a higher rate of hard endpoints like mortality and/or non-fatal acute myocardial infarction at the long-term follow-up (12% vs 2.2%, P =/< .0001).23 Also, other authors proved its utility to assess the risk of developing AKI, mainly in the ACS setting or while being exposed to cardiac surgery.24Tziakas et al confirmed the significant correlation between AMI related higher ACR levels and the development of AKI after this event (area under the ROC curve 0.72; 95%CI, 0.67-0.77). However, the authors did not report on the clinical impact of this complication on the patient’s clinical course or its association with the use of contrast during coronary angiography.25

Special attention should be paid to patients with post-angiographic AKI in the ACS setting. Several studies have shown that CIN negatively impacts the prognosis of hospitalized and long-term patients. In our population, mortality in patients with CIN was significantly higher compared to those without this disease (33% vs 1.8%).

The use of urinary ACR has been less studied in this context. Meng et al. reported that high microalbuminuria levels (ACR in between 30 mg/g and 300 mg/g) were associated significantly with the development of post-contrast acute kidney injury in patients undergoing coronary catheterization (12.1% vs. 5.0%; P = .005). A key point here that distinguishes this study from ours is that they included patients with scheduled coronary angiographies only and out of the ACS setting.26Another relevant point is that the ACR cutoff value to develop CIN was determined from the analysis of the area under the ROC curve, and its value of 20 mg/g was even lower compared to the conventional standard threshold of 30 mg/g, a finding that was consistent with what other clinical studies reported.27

The rate of CIN and its impact on the clinical outcome of coronary patients triggered the development of predictive scores for this disease. One of the best known indices is the Mehran score that includes variables like age > 75 years, hypertension, functional class III/IV heart failure, diabetes mellitus, anemia, use of intra-aortic balloon pump, volume of contrast administered, and past medical history of renal dysfunction and is capable of identifying who the most vulnerable patients are to develop post-coronary angiography CIN (the area under the ROC curve was 0.75). Adding the ACR to this score showed an even greater discriminatory power to predict post-coronary angiography CIN in patients with ACS. This would prove the practical utility of adding this index as a variable to the Mehran score.

CIN, one of the most common causes for acute nephrotoxicity, is a multi-factor event. Among its causes we should mention the direct nephrotoxic effect of the contrast substances used during endovascular procedures on the renal endothelium and the development of acute tubular necrosis. It is estimated that the nephrotoxicity of hyperosmolar contrast enhanced by the hemodynamic alterations produced by the ongoing ACS could alter vascular resistance with changes in the regulation of the release and balance of vasoactive substances like adenosine, endothelin, and nitric oxide. The damage perpetuates the slowing down of renal perfusion, spinal hypoxemia, ischemic injury, and ultimately cell death. In addition to reducing the clearance of oxidative stress products, the lower glomerular filtration rate levels increase the concentration of inflammatory mediators triggering structural alterations at renal tubular epithelium level like edema, vacuolization, and death.28^,29

We believe that these findings could help identify patients at high-risk of developing post-coronary angiography CIN in the ACS setting to promote preventive measures, behaviors, and strategies to avoid this complication.

Limitations

First, one of the main limitations of our work is its single center nature. However, we should mention that the population included was representative and covered the entire spectrum of patients with ACS admitted to our coronary care unit, which secures the internal validity and representativeness of our study. Secondly, the underpowered sample may have conditioned the appearance of false negative results due to its alpha error or lower power and stopped us from performing a proper multivariable analysis. Finally, certain data such as the volume of contrast used in each study was calculated retrospectively with the usual biases of this type of analysis.

CONCLUSIONS

The albumin-to-creatinine ratio, a recognized predictor of renal and endothelial dysfunction, was also a marker of CIN in patients with ACS with an added value when it was included in a widely validated clinical score. These results may be the beginning of a hypothesis-generating study to be confirmed prospectively at a multi-center level.

FUNDING

No funding or grants were received for this work.

CONFLICTS OF INTEREST

None declared.

ACKNOWLEDGEMENTS

We wish to thank the entire staff of the Hospital Alemán Coronary Care Unit, particularly the nursing staff who helped collect the urine samples that were crucial to conduct this study.

 

REFERENCES