A novel hybrid strategy of drug coated balloon and stent for coronary bifurcation lesions

Abstract

Background. Provisional side branch (SB) stenting strategy is the default approach for the majority of bifurcation lesions, but outcomes of SB is suboptimal. Though drug coated balloon (DCB) improving SB outcomes attracts an increasing attention, sequence of DCB hasn’t yet been determined. We presented a novel hybrid strategy of DCB and stent for bifurcation lesions. Methods. With lesion preparation, DCB was persistently inflated in SB kissing with main branch (MB) stent deployment and balloon post-dilation of the bifurcation core. Proximal optimization technique was performed strictly not exceeding the bifurcation. Procedural and clinical adverse events were evaluated. Canadian Cardiovascular Society (CCS) angina classification was assessed at baseline and clinical follow-up. Results. Fourteen patients undergoing the hybrid technique from August 2020 to July 2021 were enrolled. The technique was successfully performed in all patients without rewiring or SB compromise. Minimal lumen diameter of SB increased from 0.60 ± 0.40 mm to 2.1 ± 0.2 mm while the percent stenosis decreased from 72.4 ± 17.9% to 19.6 ± 4.7%. In addition, intravascular ultrasound indicated comparable stent symmetry index and incomplete stent apposition between proximal and distal segments of stent. No further intervention was performed, and mean fractional flow reserve of SB (n = 12) was 0.88 ± 0.05. No major adverse cardiac events was noted in hospital and 12-month follow up. The mean CCS angina score was reduced by 84% (2.2 vs 0.4, p < .001). Conclusion. The hybrid strategy facilitates treatment of DCB and stent for bifurcation lesions, which appears to be feasible and acceptable in a short-term follow-up.

Keywords:

• Coronary bifurcation lesion
• drug coated balloon
• drug-eluting stent
• fractional flow reserve
• intravascular ultrasound

Introduction

Bifurcation lesions account for up to 20% of total percutaneous coronary intervention (PCI) procedures, which is challenging due to its lower procedural success and poor outcomes [1]. Currently, the default approach for bifurcation lesions is implantation of a drug eluting stent (DES) in the main branch (MB) with provisional side branch stenting [1,2]. Despite the considerable improvement in MB, long-term outcomes of side branch (SB) treatment are suboptimal [3]. Recently drug coated balloon (DCB) improving SB outcomes attracts a striking attention in bifurcation lesions [4–6]. However, physicians are facing the dilemma about whether the SB treatment with DCB should be applied before or after MB stenting [5–11]. DCB application before MB stenting increases the risk of second stent [6–9], while DCB use after stenting causes the difficult crossing of guidewire and DCB, damage of coated drug, high drug washout and stent deformation [5,10–12]. The optimal sequence of DCB and stent has yet to be determined.

Previously, we have reported our experience for bifurcation lesion that double kissing inflation outside the stent (DKo) technique prevents SB compromise effectively without rewiring [13]. Given that, we propose a novel hybrid strategy for bifurcation lesions, which derives from the DKo technique using DCB instead of regular balloon in SB. During the inflation of DCB in SB, stent deployment and balloon post-dilation of the bifurcation core are applied. DCB plays roles in not only preventing SB from occlusion but also delivering anti-proliferative drug on the vessel wall. In this study, we investigate the feasibility and efficiency of this novel strategy for bifurcation lesions combining DCB with DES.

Materials and methods

Study population

Patients who presented with non-ST-elevation myocardial infarction or angina pectoris and underwent PCI for de novo coronary bifurcation lesions between August 2020 and July 2021 in our center were screened. The vessel size must be ≥ 2.5 mm in the MB and ≥ 2.0 mm in the SB with a visually estimated diameter stenosis > 70% involving the MB and the ostial SB on coronary angiography. SB was at a high risk of occlusion classified as Medina type 1,1,1. Patients received the hybrid strategy of DCB (Paclitaxel) and DES were included. The study was approved by Ethics Committee of Zhongshan Hospital, Fudan University (approval no: B2021-005R) and conformed to the principles of the Declaration of Helsinki. Informed consent was obtained from all the patients.

Standardized procedure

Patients received a loading dose of aspirin and P2Y12 inhibitor prior to the PCI. The standardized operation was developed at our institution, which derived from our previous work [13]. The procedure is schematically shown in Figure 1. First, coronary angiography demonstrated the true bifurcation lesion (Figure 1(A)). After advancing guidewires into branches separately, lesion preparation was performed for MB (Figure 1(B)) and SB (Figure 1(C)) with semi-compliant balloons. A proper DCB and DES were introduced and positioned, and kissing inflation was performed for 10–15 s to deploy the stent (Figure 1(D)). DCB should not protrude into MB too much, which should be located at the expansion part of the bifurcation. The stent balloon was removed when DCB was inflated persistently up to 90 s (Figure 1(E)). A non-compliant balloon was selected and inflated at the bifurcation core to optimize stent apposition kissing with the DCB for 10–15 s as the second kissing inflation (Figure 1(F)). Post-dilation balloon in MB and DCB in SB were deflated and removed, and then proximal optimization technique (POT) was performed strictly not exceeding the bifurcation core with a short noncompliant balloon to correct stent apposition using stent boost and angiography to position the balloon (Figure 1(G)). Coronary angiography (Figure 1(H)) and intravascular ultrasound were applied to confirm the final results of the bifurcation lesion.

Figure 1. Schematic image depicting the key steps of the hybrid technique. (A) Coronry bifurcation lesion. (B) Preparation for main branch. (C) Preparation for side branch. (D) Stent deployment kissing inflation with drug coated balloon (DCB). (E) Persistent inflation of DCB when removing stent balloon. (F) Balloon post-dilation of bifurcation core kissing with DCB. (G) Proximal optimization technique. (H) Final results.

Quantitative coronary angiography

Two-dimensional quantitative coronary angiography (QCA) was independently reviewed by an interventional physician, who didn’t take part in the study, and thrombolysis in myocardial infarction (TIMI) flow grading was established for the MB and SB. SB compromise was defined as TIMI 0–2 flow. QCA assessment was performed at baseline and post PCI by standard techniques with automated edge-detection algorithms (CASS-5.2, Pie Medical, Maastricht, the Netherlands) [14]. Procedure success was defined as simultaneous deployment of stent and DCB and final residual stenosis ≤30% without flow impairment or complication.

Intravascular ultrasound (IVUS) analysis

IVUS images of MB after DES implantation were measured at both distal and proximal segments of the stent. After intracoronary administration of nitroglycerin 0.2 mg, IVUS imaging was performed via motorized transducer pullback (0.5 mm/s) and a commercial scanner (Boston Scientific/SCIMED, Minneapolis, Minnesota) consisting of a rotating 40-MHz transducer within a 3.2 Fr imaging sheath. Off-line IVUS images were analyzed by an independent physician using computerized planimetry (EchoPlaque 3.0, Indec Systems, Mountain View, California). External elastic membrane (EEM), and minimum stent cross sectional area (MSA) within each of these segments were evaluated. The stent symmetry index (SSI) was calculated by dividing the minimal stent diameter (Dmin) by the maximal stent diameter (Dmax) at a cross-section with the smallest lumen cross-sectional area in the proximal and distal stent segments, as previously described [15]. Incomplete stent apposition (ISA) was defined as lack of contact between at least one strut and the underlying arterial wall intima that did not overlap a SB with evidence of blood flow behind the strut.

Functional evaluation of side branch

Fractional flow reserve (FFR) assessment of the SB was performed at the end of the procedure when the operator considered the angiographic result acceptable and final as described previously [16]. Equalization of the Pd and Pa was performed with the pressure guidewire sensor positioned at the guiding catheter tip. Next, the pressure guidewire (Abbott Vascular, Santa Clara, California) was advanced through the DES struts into the distal SB, and FFR was measured 10 mm distal to the SB ostium at maximal hyperemia induced by intravenous infusion of 10 mg/kg/h adenosine triphosphate through the median cubital vein. Hyperemic pressure pullback recordings were performed as described previously. When FFR was <0.80, residual stenosis of SB was considered functionally significant and compromised.

Clinical outcomes

Procedural and in-hospital clinical outcomes were recorded. Clinical follow-up was performed by office or telephone visit at 1, 3, 6, and 12 months. Major adverse cardiac events (MACE), as a composite of cardiac death, myocardial infarction and target lesion revascularization, were noted. In addition, Canadian Cardiovascular Society (CCS) angina classification was assessed at baseline and clinical follow-up.

Results

Baseline characteristics

Between August 2020 and July 2021, excluding two-stent technique and single-stent crossover technique, the hybrid strategy was successfully performed in 14 patients with Medina 1,1,1 bifurcation lesions located at proximal left anterior descending artery and diagonal branch according to the standardized protocol. Table 1 illustrates the baseline characteristics. Of the 14 patients, the majority of patients were male (85.7%) with a high prevalence of risk factors for coronary artery disease. Mean CCS angina score was 2.2 ± 1.0 at baseline. Renal and cardiac function were normal in all patients. The hybrid strategy was performed via radial access with 6 F guiding catheter in 6 patients and 7 F guiding catheter in 8 patients in this study.

Table 1. Clinical characteristics (n = 14).

Age, y	63 ± 10
Male, n(%)	12(85.7)
Hypertension, n(%)	8(57.1)
Diabetes, n(%)	7(50.0)
Hyperlipidemia, n(%)	4(28.6)
Smoking, n(%)	6(42.9)
Prior PCI, n(%)	1(7.1)
CCS classification
Class I, n(%)	3(21.4)
Class II, n(%)	7(50.0)
Class III, n(%)	2(14.3)
Class IV, n(%)	2(14.3)
eGFR, mL/min/1.73m^2	76 ± 8
LVEF, %	64 ± 4

Note: CCS: Canadian Cardiovascular Society.

QCA analysis

Lesion and procedural characteristics are presented in Table 2. All lesions were treated with stents of diameter ≥2.5 mm in MB and DCB of diameter ≥2.0 mm in SB. Of them, five patients received Restore (Grandpharma, Hubei, China), five patients received Bingo (Yinyi, Liaoning, China), and four patients received SeQuent Please (Braun, Melsungen, Germany) balloons. Mean diameter of DCB was 2.1 ± 0.2 mm.

Table 2. Quantitative coronary angiography assessment (n = 14).

	Main branch	Side branch
Pre-procedure
Reference diameter, mm	3.19 ± 0.33	2.27 ± 0.23
Minimal lumen diameter, mm	0.33 ± 0.20	0.60 ± 0.40
Percent diameter stenosis, %	89.8 ± 7.3	72.4 ± 17.9
Lesion length, mm	29.9 ± 12.9	9.6 ± 3.3
Procedure
Kissing stent/balloon length, mm	27.8 ± 6.3	16.8 ± 2.5
Stent/balloon diameter, mm	3.0 ± 0.3	2.1 ± 0.2
Number of stents/balloons	1.6 ± 0.5	1.1 ± 0.3
Kissing inflation pressure, atm	10.3 ± 0.7	10.3 ± 1.3
Post-procedure
Minimal lumen diameter, mm	2.95 ± 0.33	1.83 ± 0.23
Percent diameter stenosis, %	7.3 ± 2.9	19.6 ± 4.7
Acute gain, mm	2.62 ± 0.45	1.23 ± 0.48

QCA analysis showed that mean reference vessel diameters and minimal lumen diameters were 3.19 ± 0.33 mm and 0.33 ± 0.20 mm in the MB, and 2.27 ± 0.23 mm and 0.60 ± 0.40 mm in the SB. Diameter stenosis of the MB and SB was 89.8 ± 7.3% and 72.4 ± 17.9%, respectively. Mean lengths of the MB and SB lesions were 29.9 ± 12.9 mm and 7.6 ± 3.8 mm, respectively. Mean diameter and length of DES/DCB were 3.0 ± 0.3 mm and 27.8 ± 6.3 mm in the MB, and 2.1 ± 0.2 mm and 16.8 ± 2.5 mm in the SB, respectively. Kissing inflation pressure was 10.3 ± 0.6 atm in MB and 10.3 ± 1.3 atm in SB. Procedural success was achieved in all patients with residual stenosis of 7.3 ± 2.9% in MB and 19.6 ± 4.7% in SB, respectively. No SB rewiring or additional kissing balloon inflation was performed.

IVUS evaluation

Quantitative IVUS data are shown in Table 3. With successful procedure, MSA in the proximal and distal segments achieved up to 8.11 ± 1.52mm² and 6.67 ± 1.32mm², respectively. Stent symmetry index and incomplete stent apposition were similar in both segments of stents. The snapshots of MSA at both proximal and distal segments in all patients were presented in the Supplementary Figures 1–14.

Table 3. Intravascular ultrasound analysis (n = 14).

Proximal main branch
Proximal optimal technique balloon size (mm)	3.3 ± 0.4
External elastic membrane area (mm^2)	14.67 ± 3.75
Minimum stent cross sectional area (mm^2)	8.11 ± 1.52
Stent symmetry index	0.89 ± 0.03
Incomplete stent apposition (%)	1(7.1)
Distal main branch
Post-stent dilation balloon size (mm)	2.9 ± 0.2
External elastic membrane area (mm^2)	11.48 ± 3.27
Minimum stent cross sectional area (mm^2)	6.67 ± 1.32
Stent symmetry index	0.88 ± 0.04
Incomplete stent apposition (%)	1(7.1)

FFR study

Mean drug coated balloon/artery ratio in SB was 0.92 ± 0.05. The residual percent stenosis of SB lesion was < 30%. FFR was measured in SB after post-dilation of MB (n = 12) and FFR ranged between 0.81 and 0.95 with a mean value of 0.88 ± 0.05. Figure 2 shows the procedure and results of one representative case.

Figure 2. Step-by-step procedures of the hybrid technique in one representative patient. (A) Bifurcation lesion of left anterior descending artery (LAD) and first diagonal branch (D1). (B) Deployment of stent (10 atm) and DCB (10 atm). (C) Withdrawal of stent balloon but sustained inflation of DCB. (D) Post-dilation of bifurcation core (18 atm) simultaneously with DCB (10 atm). (E) Proximal optimization technique. (F) Final coronary angiography. (G) Distal and (H) proximal minimum stent cross sectional area images. (I) Fractional flow reserve test of D1. LAD: left anterior descending artery; D1: first diagonal branch; DCB: drug coated balloon.

Follow-up

No MACE events occurred in the hospital. All patients underwent at least 12-month follow-up (ranged 12–18 months). During this period, no MACE occurred. Additionally, mean CCS angina score was reduced by 84% (2.2 vs 0.4, p < .001).

Discussion

In this study, we report a hybrid strategy of DCB and DES for bifurcation lesions, which appears feasible with high rate of procedural success and favorable short-term outcomes in a small sample of patients.

PCI for bifurcation lesions is still a challenge due to the possible suboptimal results [1,2,16]. Even though DES application could improve the procedural success rate through decreasing the rate of SB compromise, restenosis rate of SB remains high and this is partly attributed to the multiple metal layers at the SB ostium [17,18]. The current practice of provisional stenting of the MB is reasonable; however, optimal therapy in SB remains a matter of considerable debate [19]. Recently, DCB use in SB has drawn an increasing attraction [20,21]. Potential advantages of DEB application in SB [12,21] are: (1) avoidance of unnecessary implantation of a stent and subsequent stent mal-apposition, incomplete coverage, overlapping and crushing of multiple metal layers, late stent thrombosis, uncontrolled drug release and reactions to a foreign body; (2) respecting the original anatomy of bifurcation and diminishing abnormal flow patterns of the bifurcation; (3) delivering homogeneous high dose of anti-proliferative drug on the entire vessel wall at the moment of injury; (4) decreasing the duration of dual antiplatelet therapy with reduced late thrombosis due to absence of polymers.

Although DCB use in SB provides a promising prospective, sequence of DCB use has not yet been determined. DCB use before MB stenting brings out a high rate of bailout stent. In the first-in-man, observational study [6], PEPCAD V study demonstrated that stent was implanted in 14.3% of SB. In the DEBIUT study [7], bailout stenting was performed in 10% of DCB treated lesions. In the BABILON trial [8], 7.8% of SBs received a stent implantation in the DCB arm. Similarly, bailout stenting of SB was 7.8% in the BIOLUX-I study [9]. These studies indicate a high risk of SB compromise during MB stenting, which result in rewiring, kissing inflation and bailout stenting. In addition, kissing inflation affects the stent deformation [22]. Bailout stenting increases the risk of delivery failure, misplacement and under-expansion of the SB stent, which could worsen the clinical outcomes [23]. An alternative is that DCB use after MB stenting, as reported in the BEYOND [5], DEBSIDE [10] and SARPEDON [11] studies. After MB stenting and kissing balloon inflation with the regular balloons, DCB is delivered and deployed in the SB. Some concerns need to be discussed in this strategy. First of all, DCB crossing stent strut is more difficult than a regular balloon due to poor profile and flexibility. Furthermore, crossing strut may damage coated drug and drug washout will increase when DCB encounters difficulty crossing the strut. Moreover, incomplete drug coverage of SB ostium could increase target lesion failure. Finally, inflation of DCB alone in SB could lead stent distortion and require potential intervention of MB stent.

Given all this, we propose the unique strategy for the bifurcation lesions combining DCB with DES, deriving from DKo technique we have reported [13]. Similar to the DKo technique, sustaining inflation of DCB in SB during post-dilation of bifurcation core prevents the residual risk of SB compromise after withdrawal of SB balloons and shows a favorable protection of SB without rewiring. In this strategy, DCB plays a protective role as regular balloon in DKo technique, and meanwhile, more importantly, it delivers anti-proliferative drug on the entire vessel wall. Compared with prior both strategies, our hybrid strategy has some potential advantages. (1) Post-dilation of bifurcation core is performed as kissing inflation with DCB, which prevents SB compromise. One hundred percent patency of SB is similar to our previous work [13]. The major mechanisms of SB occlusion are carina shift and plaque shift [24], which is prevented by persistent inflation of DCB during MB stenting and post-dilation of bifurcation core. (2) Rewiring and additional intervention in previous technique is sometimes challenging. The hybrid strategy can simplify the procedure, reduce its difficulty, shorten procedure time, reduce radiation exposure and decrease contrast media [18]. (3) Guidewire recrossing point influenced the ISA and SB restenosis [25]. Asymmetrical stent deformation and overstretch of the proximal stent (“geographic loss”) caused by kissing balloon inflation are associated with strut mal-apposition, vessel dissection/injury, and more severe neointimal stretching hyperplasia or arterial stretching [15,26]. Kissing balloon inflation fails to provide benefits with unsatisfactory angiographic and clinical outcomes [27]. Similar to DKo technique [13], this hybrid technique could avoid stent overexpansion and induce rare impact on ISA and SSI, which may improve clinical outcomes. (4) Though pre-dilation of SB is probably not necessary in some cases, it should be performed in order to simplify the procedure when SB compromise after MB stenting is highly anticipated [28]. We integrate pre-dilation with balloon protection and drug delivery in one step, which brings out great result in this study. Therefore, this technology simplifies therapy in bifurcation lesions and is worthy of popularizing and applying.

There are some concerns in this hybrid strategy that need to be noted. (1) The poor profile and flexibility of DCB demands sufficient pre-dilation [9,12]. (2) Separate short DCBs are more appropriate for diffuse SB lesion than a long DCB, which is recommended. The hybrid strategy is performed with a short DCB at the SB ostium. Abovementioned tips facilitate position of DCB, shorten delivery time and reduce drug washout. (3) DCB diameter sized at a 0.8–1.0 ratio to the artery diameter and poorer profile over regular balloon increase the friction between the DCB and stent, and thus special care needs to be taken to withdraw the DCB to avoid injury of guiding catheter and guidewires. The diameter of DCB in the hybrid strategy is selected according to SB diameter to uniformly deliver antiproliferative drug over SB walls. No balloon entrapment or device related complications occurred in our study. (4) Kissing balloon inflation via a 6 Fr guiding catheter with a DCB needs to be concerned, which was easily performed in our and other studies [29,30]. (5) Stent symmetry and apposition is corrected by POT after DCB withdrawal, which has been illustrated by intravascular imaging [13,31]. (6) Clinicians also concern about the residual stenosis of SB ostium. Koo et al. [32] reported FFR > 0.75 in < 75% stenosis of SB ostium. Similarly, residual stenosis of SB ostium < 50% and FFR > 0.80 were recorded in this study.

Several limitations need to be stated in this study. This is a retrospective, observational study with the small sample size in a single center. It is an explorative strategy and has been applied in only 14 cases with proximal LAD and diagonal branch by a few operators in our center. Due to pilot attempt to use this hybrid technique, we just selected 14 relatively simple cases without obvious tortuosity or calcification and the technique was successfully performed in all cases. Therefore, explanation of the results should be cautious. But this strategy is based on our previous DKo technique [13], which included 117 patients and offered good protection for SB. Calcific lesions have higher probability of SB occlusion [33] and potentially cause device entrapment [27]. In our experience, no SB occlusion or device entrapment might be due to the small sample size and simple lesions without obvious tortuosity or calcification. Physicians should pay more attention to avoid device entrapment and prevent device related injury when it is used in severe calcific lesions. Moreover, the study reported short-term outcomes and didn’t compare with current DCB strategies. The long-term outcomes require further controlled studies with larger population.

The hybrid strategy of DCB and stent for bifurcation lesions is feasible and acceptable in a short-term follow up in a small sample of patients, which may be a better way of DCB usage in theory and warrants further studies to confirm.

Author contributions

Concept—HY, ZH, FZ; design—HY, ZH; supervision—JQ, JG; funding—HY, ZH, JG; materials—ZH, FZ; data collection and/or processing—YS, JC, JC; analysis and/or Interpretation—HY; literature review—JQ, ZH; writing—HY; critical review—JG.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings of this study are available from the corresponding author, Zheyong Huang, upon reasonable request.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China [Grants number 81801374, 82070281], Shanghai Clinical Research Center for Interventional Medicine [Grant number 19MC1910300], Shanghai ‘Rising Stars of Medical Talent’ Youth Development Program [Grant number 2019-72] and Key Clinical Research Projects of National Clinical Research Center for Interventional Medicine [Grant number 2021-005].