Drug-Eluting Balloon for Management of Coronary In-Stent Restenosis in a South Asian Population: Experience From a Tertiary-Care Hospital in Pakistan

Abstract. Background. Emerging evidence suggests that the South Asian (SA) population has an increased rate of in-stent stenosis (ISR) after percutaneous coronary intervention (PCI) when compared with other ethnicities. Drug-eluting balloons (DEBs) have emerged as a viable option for the treatment of ISR. However, data describing the outcomes of DEB-PCI in the SA population are limited. Since the magnitude of the problem is high in the SA population, it is essential to evaluate the outcomes of DEB-PCI for ISR. Methods. In this cohort study, we investigated the incidence of target-lesion revascularization (TLR) and major adverse cardiac event (MACE) after PCI with DEB for ISR at 1 year and at long-term follow-up in Pakistani patients. From January 2010 to January 2019, a total of 147 ISR lesions in 112 patients were treated with DEB-PCI at our center. Results. The incidence of clinically driven TLR and MACE after a 1-year follow-up was 15.2% and 16.1%, respectively. At mean long-term follow-up of 2.73 ± 2.14 years, the TLR and MACE rates were 26.8% and 35.7%, respectively. The major predictors for TLR were diffuse and occlusive ISR types, DEB for a recurrent restenosis lesion, and the presence of ≥3 traditional cardiovascular disease risk factors. Conclusions. The high rates of follow-up TLR and MACE reported in this study may suggest that the outcomes of DEB-PCI for ISR in the SA population may be unsatisfactory. With the increasing use of DEBs, it is imperative to further investigate DEB-PCI outcomes in the SA population with large, prospective studies.

J INVASIVE CARDIOL 2021;33(2):E127-E134. Epub 2020 December 6.

Key words: drug-eluting balloon, drug-coated balloon, in-stent restenosis, South Asian population

In-stent restenosis (ISR) is the bane of percutaneous coronary intervention (PCI) in the stent era. Initially thought to be a complication of bare-metal stenting (BMS), it prompted the introduction and the subsequent rise of drug-eluting stenting (DES) as the modality of choice for PCI. Although with the advent of DES there has been a progressive decline in the rate of ISR, it still remains one of the main reasons for PCI failure in the modern era.¹

The optimal management of ISR itself remains a clinical challenge worldwide, with various techniques and devices proposed for its treatment. A relatively novel device known as the drug-eluting balloon (DEB) has emerged as an attractive option for the treatment of ISR lesions.² These semicompliant balloons, which are coated with antiproliferative drugs, work similar to DES but without the metal polymer, thereby decreasing the cascade of chronic inflammation and neointimal formation; consequently, delaying the restenosis process.³ The clinical efficacy of DEB-PCI is found to be favorable in randomized clinical trials and “real-world” registry data.^4-7 As a result, the current European Society of Cardiology guidelines endorse the use of DEB for the management of ISR.⁸ 

The South Asian (SA) population is known to have a higher burden of coronary artery disease (CAD), which occurs at a younger age, and is clinically advanced with angiographically extensive disease (3-vessel CAD).⁹ Evidence also suggests that SA patients have a higher rate of ISR when compared with the Caucasian population and the Chinese population.^10-12 Studies describing the use of DEB for coronary ISR management from SA countries are limited. A previous study from Pakistan reported a high rate of major adverse cardiac event (MACE) at follow-up.¹³ Another study from India described a high rate of target-lesion revascularization (TLR) at 6-month follow-up.¹⁴ However, both of these studies were limited in their sample size (n<30); consequently, the outcomes of DEB-PCI in SA patients are largely unknown. Since the patient demographics and pattern of CAD are different in the SA population, we sought to evaluate the outcome of DEB-PCI for ISR in a larger SA cohort.

Methods

Inclusion criteria and data collection. This was a single-center, retrospective cohort study conducted at the Aga Khan University Hospital Karachi in Pakistan. All patients who had PCI with DEB for the indication of ISR at our hospital from January 2010 to January 2019 were identified through the Hospital Information Management System (HIMS) and included in our study. For the purpose of this study, ISR was defined as ≥50% diameter stenosis by visual assessment on invasive coronary angiography within a previous stent and/or 5 mm outside of the stent. Data regarding patient characteristics, procedural details, and in-hospital outcomes were collected from HIMS and review of the hospital charts. Patients with missing data were excluded. The local ethics review committee approved the study.

PCI procedure. According to the hospital’s catheterization laboratory protocol, all patients planned for PCI (either elective or while in acute coronary syndrome [ACS]) were pretreated with 300 mg aspirin and 300 mg or 600 mg clopidogrel. The choice of anticoagulation in ACS and for PCI at our institute is intravenous (IV) unfractionated heparin; hence, all patients received a body-weight adjusted dose of IV heparin (100 IU/kg body weight) prior to PCI. The use of glycoprotein IIb/IIIa inhibitor was at the discretion of the interventional cardiologist. All invasive coronary angiograms and PCIs were performed using standard techniques and according to contemporary practice guidelines. The PCI with DEB was performed by experienced interventional cardiologists in patients presenting with angiographic evidence of ≥50% luminal diameter stenosis on visual assessment within a previously placed stent and/or 5 mm outside of the stent. All lesions were prepared with predilation using a conventional balloon with a balloon-to-vessel ratio of 0.8-1.0. Then, the paclitaxel-coated balloon (SeQuent Please; B. Braun), which exceeded the target lesion proximally and distally, was applied and kept inflated for at least 30 seconds with a pressure of at least 8 atm. PCI complications were defined as coronary or aortic dissections, vessel occlusion, intracoronary thrombosis, and coronary perforation as judged by the treating cardiologist. Technical failure was defined as delivery failure of DEB, flow-limiting dissection (Thrombolysis in Myocardial Infarction [TIMI] <3), significant recoil (>30% in main branch or >50% in a side branch) or bailout stenting after DEB for a PCI complication. Angiographic success was determined by whether the treating vessel had <50% residual stenosis with normal flow after DEB with or without additional stenting. Patients were prescribed 75 mg of aspirin and 75 mg of clopidogrel for at least 1 year post DEB-PCI unless contraindicated.

Follow up, endpoints, and definitions. Clinical follow-up data of all included patients were obtained from clinic visits or telephoned interviews. Routine angiographic follow-up of the patients was not done. All patients completed at least 1-year of follow-up (except those who had mortality within 1 year). For the patients who died, the next of kin were interviewed and death certificates obtained to determine when the death had occurred.

Primary endpoints were ischemia-guided TLR of the DEB-PCI lesion and MACE, defined as a composite of cardiac death, myocardial infarction (MI), and TLR during the follow-up period. TLR was defined as any repeat PCI of the previous DEB-PCI lesion (target) or bypass surgery of the target vessel because of restenosis of the target lesion. MI was defined by typical clinical symptoms, relevant electrocardiographic changes, and/or elevated troponin T or troponin I. All deaths were considered to be cardiac in origin unless a clear non-cardiac cause could be established.

Statistical analysis. Statistical analysis was performed with the use of the Statistical Package for Social Sciences, version 24.0 (IBM Corporation). Continuous variables were expressed as mean ± standard deviations or median (interquartile range [IQR]), as appropriate. Categorical variables were expressed as absolute frequencies and percentages and compared using the Chi-squared test. Continuous data were compared using an independent-samples t-test or the Mann-Whitney U-test, depending on their distribution. The multivariate regression analysis was performed using the binary log-regression model to evaluate predictors for TLR at 1 year and mean follow-up, in which each entered variable had P-value <.10 based on univariate analysis. A 2-sided P-value of <.05 was considered statistically significant for all tests. 

Results

From January 2010 to January 2019, a total of 147 ISR lesions in 112 patients were managed with PCI using DEBs at our center. Most of the lesions treated were ISR in a previously placed DES (103 lesions, 75 patients). Table 1 shows the baseline patient characteristics of the study patients. The traditional risk factors for CAD were high among patients, with the highest risk factor being hypertension (93.2%) followed by diabetes mellitus (74.1%). The majority of patients (73.2%) presented with ACS, with the numbers slightly higher in the DES-ISR patients. Three-fourths of the total patients had multivessel CAD on coronary angiogram. Baseline characteristics of the ISR lesions are reported in Table 2. The left anterior descending coronary artery was the most common target vessel for DEB-PCI, in 44.9% of the total ISR lesions treated. Only 12 lesions (8.2%) had DEB-PCI for branch vessel ISR lesions, ie, diagonal, obtuse marginal, posterior descending artery, posterior left ventricular artery, and ramus. It was seen that BMS lesions had a significantly longer mean time to ISR (6.56 ± 5.54 years) as compared with DES lesions (3.09 ± 2.87 years). A total of 25 lesions (17.0%) were treated for recurrent ISR, ie, ISR lesions that had >1 previous intervention of the target lesion before the index DEB intervention. The mean diameter of the target vessels was 2.94 ± 0.45 mm and the mean target-lesion length was 19.83 ± 5.70 mm, with no significant differences between the BMS-ISR and DES-ISR lesions. PCI with DEB was also used to treat complex ISR lesions, with 21 bifurcation and 9 chronic total occlusion (CTO) lesions treated. Of the total ISR lesions treated, 53.1% had a previous everolimus-eluting stent in place. The most frequent type of ISR encountered was focal type (58.5%) followed by diffuse type (27.9%); this was similar in the BMS-ISR and DES-ISR groups. 

The procedural characteristics of ISR lesions are summarized in Table 3. The mean DEB length used was 22.37 ± 5.82 mm with a mean diameter of 2.95 ± 0.43 mm. The mean inflation pressure was 10.54 ± 2.84 atm. Twenty lesions (13.6%) required additional stenting with either a BMS or DES due to technical failure. A total of 4 PCI complications after DEB deployment were seen; 2 were due to abrupt formation of intracoronary thrombus and 2 were due to coronary artery dissection. Angiographic success was achieved in 97.27% of the total lesions treated. PCI to a non-target vessel with either a BMS or DES was performed concomitantly with 59 DEB target lesions. The procedural characteristics were similar in the BMS-ISR and DES-ISR groups. 

The mean follow-up for the entire study cohort was 2.7 ± 2.14 years. None of the patients with DEB intervention had in-hospital MI or mortality. Figure 1 summarizes the follow-up TLR and MACE outcomes of the study group after PCI with DEB for ISR lesions. Ischemia-guided TLR was done for 23 lesions (15.6%) in 17 patients (15.2%) within 1 year of follow-up. At mean follow-up, 38 lesions (25.9%) in 30 patients (26.7%) had ischemia-guided TLR. The TLR rates were similar in both BMS and DES groups. Almost all patients who underwent TLR had presented with an MI. The overall mortality at mean follow-up was 20.5% while the cardiac mortality at mean follow-up was found to be 10.7%. MACE had occurred in 18 patients (16.1%) at 1-year follow-up, and in 40 patients (35.7%) at long-term follow-up. MACE at 1-year follow-up was slightly higher in the DES-ISR group vs the BMS-ISR group (17.1% vs 13.5%, respectively). The MACE in both groups was driven by TLR.

The univariate analysis of different factors to predict TLR at 1 year and TLR at long-term follow-up is described in Table 4. Factors with a P-value <.10 were added to the log-regression analysis for multivariate analysis (Table 5). Diffuse and occlusive ISR types emerged as strong predictors of TLR at 1 year (odds ratio [OR], 4.5; 95% confidence interval [CI], 1.4-13.9 and OR, 4.6; 95% CI, 3.1-55.8, respectively). Diffuse ISR lesions treated with DEB also had a higher risk of TLR at long-term follow-up (OR, 13.2; 95% CI, 3.1-55.8). DEB-PCI for recurrent stenosis was found to be a predictor of TLR within 1 year (OR, 3.9; 95% CI, 1.3-11.3); however, it was not found to be a predictor for long-term TLR. History of hypertension, diabetes mellitus, dyslipidemia, and smoking did not emerge as independent predictors of TLR at either 1 year or at long-term follow-up, even though patients with diabetes mellitus had greater odds of having TLR. However, a composite of these 4 traditional risk factors did emerge as a strong predictor of 1-year and long-term follow-up TLR.

Discussion

The results of this investigation reveal a higher rate of TLR and TLR-driven MACE at 1-year and long-term follow-up after PCI with DEB for ISR in an SA study population compared with registry studies.^15-17 The benchmark SeQuent Please worldwide registry, which had an unknown number of SA patients, reported considerably lower rates of TLR for BMS-ISR (3.8% vs 13.5%) and DES-ISR (9.6% vs 16%) at 9 months of follow-up.¹⁷ A possible reason for the higher TLR rate in our study could be the different clinical profile of the patient population. In comparison with the SeQuent Please registry, our study had a higher number of patients with diabetes mellitus (74.1% vs 36%). The effects of a higher prevalence of diabetes mellitus in our study group were also seen in the clinical presentation of the patients, with 73.2% of our study cohort presenting as ACS, while only 14% of patients had ACS presentation in the SeQuent Please registry. In our study, patients had angiographically advanced CAD, which was evident by the longer lesions (19.83 ± 5.70 mm vs 17.3 ± 8.0 mm in the SeQuent Please registry), and hence longer DEBs that were required to treat them (22.37 ± 5.82 mm vs 20.3 ± 5.5 mm in the SeQuent Please registry). Most of the lesions treated in our study were in the DES-ISR group, while the majority of treated lesions were BMS-ISR in the SeQuent Please registry. Intracoronary thrombus was found in 11.6% of our patients compared with 2.9% in the SeQuent Please registry. 

However, the high TLR rates are not completely explained by the differences in clinical characteristics. A Chinese registry reported a 1-year TLR rate of 6.3% in DES-ISR patients even though they had a higher number of ACS patients (94.8%).¹⁸ A registry from Singapore that described the use of longer DEBs (24.0 ± 11.1 mm vs 22.37 ± 5.82 mm) and had a comparable ACS presentation (75.6%) reported an extremely low TLR rate of 4%.¹⁹ The higher TLR rates in our study may be explained by the ethnic differences between the study populations. 

In the present study, we also investigated the predictors of TLR at 1-year and mean long-term follow-up in our population. One of the independent predictors for TLR in our study was PCI with DEB for diffuse and occlusive ISR types. This result was similar to other studies that have reported worse outcomes for PCI with DEB for non-focal ISR lesions.^15,20,21 Another predictor of TLR at 1-year follow-up in our study is the use of DEB to treat recurrent ISR. Recurrent ISR is defined as a second ISR event after the successful treatment of an initial ISR lesion.²² The optimal treatment for recurrent ISR is still unknown and the efficacy of DEB-PCI for its management is still under exploration.²³ Yabushita et al recently investigated the effect of multiple stent layers on the outcomes of DEB-PCI for ISR.²⁴ The results showed that TLR at 1 year for ≥3 stent layers was significantly higher (41.2%) compared with 2 layers (14.9%) and 1 year (14.9%). It also reported that ≥3 stent layers and patients on maintenance hemodialysis were strong predictors of MACE at follow-up. Interestingly, in our study, individual risk factors for CAD, namely, diabetes mellitus, hypertension, smoking, and dyslipidemia, did not emerge as predictors for TLR after multivariate analysis. However, patients who had ≥3 of these traditional risk factors had a higher risk of TLR at 1 year as well as at long-term follow-up. The SeQuent Please registry determined the predictors of TLR to be ACS, ostial lesions, and DES-ISR. However, our study did not show these to be independent predictors of TLR. Other predictors that did not appear in our study, but are reported in the literature are age >60 years,¹⁸ DEB in a previous graft ISR,¹⁷ right coronary artery ostial lesions,²⁰ longer lesions, and smaller vessel size.²⁵

The results from this study indicate that DEB-PCI in a SA population has differing results when compared with the rest of the world. The higher rates of TLR and MACE at both 1-year and long-term follow-up in our study population may reflect the growing realization that SA patients do not fare as well as other ethnicities after coronary interventions. The probable reason for this is the interplay of different risk profiles, presentation of CAD, angiographic findings, and possible genetic predisposition to recurrent restenosis. However, larger prospective registries and trials in the backdrop of ethnic differences are required to further investigate this notion.

Study limitations. Several limitations of this study must be acknowledged. First, this study is a retrospective analysis done at a single center, and hence it was subject to selection and operator bias. Second, we did not perform routine angiographic follow-up, which may have influenced the timing of TLR. Finally, we did not have a control group for comparison of our results.

Conclusion

This extensive retrospective analysis reports the outcomes of PCI with DEB for ISR lesions in a SA population. With the increasing endorsement of PCI with DEB in the interventional setting, these data are the largest attempt from SA to document the impact of DEB-PCI in the context of ISR. Although there are some limitations, we feel our study successfully attempts to identify the indicators of TLR in the SA population and provides the framework for a large, prospective review on DEB practice in this part of the world.

From the Section of Cardiology, Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Final version accepted April 3, 2020.

Address for correspondence: Osman Faheem, MD, FACC, Section Head, Assistant Professor, Aga Khan University Hospital, Section of Cardiology, Department of Medicine, Main Stadium Road, Karachi, Sindh 75500, Pakistan. Email: osman.faheem@aku.edu

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