Abstract
Background
Although the safety and effectiveness of Drug-Eluting Stents (DES) has been established extensively, reports on long term clinical outcome with angiographic findings in patients with long coronary artery lesions are not many.
Methods
In this single-center prospective registry of 100 patients, a total of 110 denovo long lesions (>20 mm) were treated with Resolute Zotarolimus Eluting Stent (R-ZES). The patients were followed up clinically at 3, 6 and 12 months and follow up coronary angiography was performed at 9-months. The primary end point was one year rate of target lesion failure (TLF) which is a composite of cardiac death, target lesion myocardial infarction or ischemia driven target lesion revascularization (TLR). The secondary end points included definite or probable stent thrombosis, 9-month angiographic restenosis and late lumen loss.
Results
The mean age of patients was 58.7 ± 9.50 years with prevalence of diabetes as high as 60%. The mean lesion length was 24.67 ± 4.87 mm with a mean reference vessel diameter of 2.85 ± 0.32 mm and 67.3% were Type C lesions (ACC/AHA classification). Two patients died during follow-up, of which one was non-cardiac death. One patient had target vessel myocardial infarction and five patients (4.5%) had ischemia driven TLR. The incidence of TLF was 6.36%. Binary restenosis was seen in 7 out of 93 lesions (7.5%). Median late lumen loss at 9 month was 0.22 mm. No stent thrombosis was noted in the study.
Conclusion
Implantation of R-ZES in real-world patients with long coronary artery lesions is safe with comparable efficacy to what is observed in the treatment of less complex lesions.
Keywords: Zotarolimus Eluting Stent, Long lesion, Target lesion failure, Late lumen loss, Stent thrombosis
1. Introduction
Long coronary artery lesions comprise up to 20% of percutaneous coronary intervention (PCI) and it is an important determinant of unfavorable outcomes after stent implantation.1 Although widespread use of early generation drug eluting stent (DES) has resulted in beneficial outcome of PCI in general, the overall major adverse cardiac events (MACE) in the treatment of long lesion remained relatively high.2 Use of new generation DES of 38 mm length to cover long lesion has been found to be safe and efficacious during one year follow-up.3,4 Various randomized clinical trials and registries have shown better safety and efficacy outcomes with the use of new generation DES in treating long lesions with either single or overlapping stents in comparison to first generation DES.5,6
However there is paucity of data on the outcomes of treating long lesions with DES in a real world scenario, involving patients with different clinical presentations, risk factors and varying complexity of lesions. This prospective study was undertaken to evaluate safety and efficacy and 12 month follow-up outcome of Zotarolimus Eluting Stent (PSEZES) in treating a cohort of patients with long lesions who present for intervention in day-to-day clinical practice.
2. Materials and methods
PSEZES was a single centre, prospective, open label, non-randomized study of Resolute Zotarolimus Eluting Stent (R-ZES) in long coronary artery lesion, conducted at Cardiovascular Centre of Ananthapuri Hospitals and Research Institute, Thiruvananthapuram, Kerala, India. The study was conducted from June 2010 to September 2012 after getting the approval of Institutional Ethics Committee. All patients provided written informed consent for participation in the study.
This study included male or female patients >18 years of age with Stable Ischemic Heart Disease (SIHD) or acute coronary syndrome (ACS). Patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI, myocardial infarction (MI) within 72 h, cardiogenic shock, left ventricular ejection fraction less than 30%, stroke within 6 months, severe renal or hepatic failure, known hypersensitivity to Zotarolimus or other drugs which could be used in the study, coagulopathy, and patients not willing to sign consent form, were excluded from the study.
The angiographic inclusion criterion was a target lesion of more than 20 mm in length with a diameter stenosis of ≥50%. The stent length was chosen to adequately cover the lesion, extending 2–4 mm beyond the proximal and distal ends. All patients were started on dual antiplatelets and other guideline recommended drugs. PCI was performed as per standard protocol. Eighty percent of the PCI were done through radial access. Pre dilation of the lesion was done in majority of the cases and high pressure post dilatation of the stent was done in all cases. A 12-lead ECG, serum concentration of creatine kinase and its MB isoenzyme were measured before stenting and twice after stenting with 8 h interval.
After discharge from the hospital, patients were followed up clinically at 3, 6 and 12 months. Follow up Coronary angiography was performed at 9-month. Clinical and angiographic follow up of patients is shown in Fig. 1.
Fig. 1.
Patient follow-up in PSEZES trial.
3. Study end points
The primary endpoint was target lesion failure (TLF) at one year after the procedure, a composite of cardiac death, target vessel myocardial infarction or target lesion revascularisation (TLR) by percutaneous or surgical methods. Secondary end points included 9-month angiographic binary restenosis, 9-month angiographic in-stent late loss and definite or probable stent thrombosis (ST). All deaths were considered cardiac unless an unequivocal non-cardiac cause could be established. A diagnosis of MI was based on the appearance of new Q wave or ST changes in at least 2 contiguous leads in the post procedure ECG or an elevation of creatine kinase MB concentration >3 times the upper limit of normal following the PCI. Revascularization of the target lesion was considered ischemia driven if there was ≥50% diameter stenosis of the target lesion with ischemic signs or symptoms or diameter stenosis ≥70% with or without documented ischemia. Stent thrombosis was defined as definite or probable by Academic Research Consortium definition.7
Coronary angiograms were recorded digitally at baseline, immediately after the procedure and at 9-months follow up, using Siemens AXIOM artis Cath Lab system. Off-line QCA analysis was performed with an automatic edge-detection algorithm (CAAS II systemic, Pie Medical, Maastricht, The Netherlands) as described before.1,8 Secondary endpoints of the study like binary restenosis was defined as >50% diameter stenosis over the entire stent length and its 5 mm proximal and distal margins on follow up and late luminal loss was calculated as the difference between minimal lumen diameter (MLD) post intervention and at follow up. Device success was defined as a final stenosis of <30% of the vessel diameter after implantation of the assigned stent.
4. Data analysis
Data was entered and analyzed using Microsoft Excel. Qualitative variables included those related to risk factors, previous history, clinical presentation and lesion details and were expressed as frequencies and percentages. Quantitative variables-mainly angiographic details at three time-points were expressed as median and Inter-quartile Range (IQR).
5. Results
Between 01 June 2010 and 19 Sep 2012, 100 patients were recruited, in whom 110 long lesions were treated. The mean age of patients was 58.7 ± 9.5 years. The baseline clinical characteristics are shown in Table 1. It is noteworthy that diabetes mellitus was present in 60% of the population and 59% had ACS at presentation. This in general, represents the clinical features of patients undergoing PCI in our centre with high proportion of ACS and diabetes mellitus. The lesion distribution is shown in Fig. 2, lesion details and stent details in Table 2. Overall, 67.3% lesions were Type-C lesions (ACC/AHA classification), 68.2% were <2.75 mm in diameter and 40.9% were ≥25 mm in length. 55.4% lesions received stents ≥30 mm in length. Major side branch was present at the lesion site in 54 (49%) lesions. Out of 54 bifurcation lesions 41 required an additional guide wire to protect the side branch, but no lesion required a side branch stenting. There was no overlap stenting in any lesions. The rate of device success was 100%. There was no significant peri-procedural bleeding or in-hospital death.
Table 1.
Baseline clinical characteristics of the patients (n = 100).
| Characteristics | Value |
|---|---|
| Mean age in years | 58.7 ± 9.5 |
| Male | 85% |
| Body-mass index (in kg/m2) | 32.29 |
| Risk factors | |
| Obesity | 88% |
| Diabetes mellitus | 60% |
| Hypertension | 60% |
| Dyslipidemia | 38% |
| Smoking | 26% |
| Previous history | |
| Previous myocardial infarction | 33% |
| Previous coronary angioplasty | 11% |
| Previous bypass surgery | 4% |
| Congestive Heart Failure | 3% |
| Prior stroke(before 6 months) | 3% |
| Peripheral arterial disease | 1% |
| Clinical presentation | |
| ACS | 59% |
| Chronic stable angina | 31% |
| Inducible ischemia | 10% |
Fig. 2.
Lesion distribution (n = 110). RCA-Right coronary artery; LCX-Left circumflex artery; LAD-Left anterior descending artery.
Table 2.
Lesion and stent details (n = 110).
| Details | Value |
|---|---|
| Lesion length (mm) | |
| 20–25 mm | 59.1% |
| 25–30 mm | 21.8% |
| 30–35 mm | 15.4% |
| >35 mm | 3.6% |
| Mean lesion length | 24 mm |
| Lesion characteristics | |
| Eccentric lesions | 97.2% |
| Moderate tortuosity | 6.3% |
| <45 degree angulations | 83.6% |
| Irregular contour | 92.7% |
| Calcification | 13.6% |
| Total occlusion | 12.7% |
| Ostial lesions | 7.2% |
| Thrombus | 3.6% |
| Lesion class C | 67.3% |
| Bifurcation | 49% |
| Lesion distribution across vessels | |
| Proximal LAD | 40% |
| Mid LAD | 16.4% |
| Distal LAD | 7.8% |
| Diagonal | 2.7% |
| Proximal LCX | 4.5% |
| Distal LCX | 2.7% |
| OM | 3.6% |
| Proximal RCA | 11.8% |
| Mid RCA | 6.4% |
| Distal RCA | 2.7% |
| RPLB | 1.8% |
| Stent length | |
| 24 mm | 44.5% |
| 30 mm | 34.5% |
| 38 mm | 20.9% |
Clinical follow-up was 100% as per scheduled intervals. Eighty four patients underwent follow-up coronary angiography. Two patients died during the follow-up, of which one was non-cardiac death resulting from sepsis during hemodialysis. One patient had target vessel myocardial infarction. Five patients (4.5%) had ischemia driven TLR. The incidence of TLF was 6.36% (Fig. 3). Nine-month follow-up angiographic analysis of 93 study stents in 84 patients showed binary restenosis in 7 patients (7.5%), with a median late lumen loss of 0.22 mm. There was no significant difference in target lesion failure, or late lumen loss across different stent sizes or diabetic vs. non-diabetic group. No stent thrombosis was noted in this study. Angiographic details are given in Table 3.
Fig. 3.
Primary end points at one year in PSEZES (n = 110). MI-Myocardial Infarction; TLR-Target lesion revascularization; TLF-Target lesion failure.
Table 3.
Angiographic details.
| Numbers | Median | IQR | |
|---|---|---|---|
| Mean RVD in mm | |||
| Pre procedure | 110 | 2.8 | 2.67–3.18 |
| Post procedure | 110 | 3.06 | 2.9–3.33 |
| At 9 months | 93 | 3.08 | 2.9–3.36 |
| Lesion length in mm | 110 | 23.76 | 20.43–26.64 |
| Diameter stenosis in % | |||
| Pre procedure | 110 | 83.0 | 78.0–88.0 |
| Post procedure | 110 | 11.0 | 8.0–13.0 |
| At 9 months | 93 | 20.0 | 15.0–26.5 |
| MLD in mm | |||
| Pre procedure | 110 | 0.47 | 0.32–0.64 |
| Post procedure | 110 | 2.72 | 2.55–2.97 |
| At 9 months | 93 | 2.45 | 2.18–2.69 |
| Late loss in mm (at 9 months) | |||
| Total population | 110 | 0.22 | 0.13–0.415 |
| Diabetics | 66 | 0.3 | 0.15–0.56 |
| Non-diabetics | 44 | 0.2 | 0.12–0.46 |
| 38 mm stents | 23 | 0.24 | 0.15–0.36 |
| <38 mm stents | 87 | 0.22 | 0.13–0.38 |
| Stents ≤2.75 mm | 45 | 0.23 | 0.14–0.49 |
| Stents >2.75 mm | 65 | 0.22 | 0.13–0.40 |
6. Discussion
Long coronary artery lesions constitute an important subgroup of PCI patients who are at increased risk for restenosis and adverse clinical events on follow up. The length of coronary lesion has been a predictor of restenosis after balloon angioplasty. In a cohort of patients with long lesions (>15 mm) use of bare metal stents (BMS) reduced the incidence of binary restenosis compared to balloon angioplasty (36.9% vs. 27.9% p < 0.001). Among patients treated with BMS, lesion length, use of multiple stents and overlapping stents were found as independent predictors of restenosis. Patients with long lesions showed more late lumen loss than those with short lesions (1.29 + 0.89 vs. 1.07 + 0.77 mm p < 0.001).9 Randomized controlled trials have shown that, early generation DES have resulted in considerable reduction in restenosis and the need for repeat revascularization compared to BMS. TAXUS VI study revealed a TLR rate of 9.1% in the Paclitaxel Eluting Stent (PES) group compared to 19.4% in the BMS group (p = 0.0027). Mean lesion length in the study was 20.6 mm and mean stent length was 33.4 mm 55.6% of the lesions were type C of the ACC/AHA classification. Binary restenosis was 32.9% in the BMS group and 9.1% in the PES group.2
In PSEZES trial the mean lesion length was 24 ± 4.8 mm and 67.3% were having Type C lesions. Use of new generation R-ZES resulted in a relatively lower binary restenosis of 7.5%. Mean stent length used in our study was 28.74 ± 5.2 mm and overlapping stents were avoided. Schoefer et al compared Sirolimus Eluting Stent (SES) with BMS in lesions longer than 15 mm length with a vessel diameter of 2.5–3.0 mm and found lower binary restenosis rate with SES (5.9% vs. 42.3% p = 0.0001) and fewer MACE rate at 9 months (8.0% vs. 22.6% p = 0.0002) mainly due to a reduction in the need for TLR (4.0% vs. 20.9% p < 0.0001).10
The LONG-DES registry and LONG-DES II randomized trial also revealed superiority of SES over PES in reducing angiographic restenosis in patients with long lesions.11,12 LONG-DES III Trial randomized patients with long lesion (>25 mm) to treatment with Everolimus Eluting Stent (EES) and SES. EES implantation was associated with greater angiographic in-segment late loss and higher rate of in-segment restenosis compared with SES implantation. However there was no difference in the clinical outcomes noted.13 Although the inclusion criteria of lesion length in our study was >20 mm in length, 45 lesions (40.9%) were >25 mm in length.
LONG-DES IV Trial compared R-ZES with SES in native long coronary lesions and found no significant difference in 9 month in-segment and in-stent late luminal loss, binary restenosis, and clinical events between the two stents.5 In LONG-DES IV trial 9 month angiographic in-stent binary restenosis was 4% and late lumen loss was 0.26 ± 0.36 mm in the R-ZES group which was relatively less compared to PSEZES outcome. But it should be noted that the R-ZES cohort of LONG DES IV had only 27.2% diabetics compared to 60% diabetics in the PSEZES trial. Similarly mean RVD of the R-ZES group was 3.25 ± 0.47 mm compared to 2.84 ± 0.32 mm in the PSEZES patients. So relatively high late lumen loss in PSEZES trial could be due to the fact that majority of the patients are diabetic with small vessels.
New generation DES in general are associated with better clinical and angiographic outcomes in long lesions even while covering the entire lesion with long stents. A stent length >32 mm was significantly associated with higher cumulative rate of TLR and ST in patients treated with first-generation DES but not with New-Generation DES.14 In our study, 61 lesions (55.4%) received stents >30 mm in length and no ST was observed and TLR was only 4.5%. Lee et al reported on the use of 38 mm R-ZES in treating long lesions, with low rate of TLF and ST and no difference in outcomes between patients with and without diabetes.6 In our study 23 patients received 38 mm stent, but no ST was noted. Jon Suh et al observed that, stent length was an independent predictor of ST. The stent length >31.5 mm was associated with higher rates of ST (4.05 vs. 0.7% p < 0.001), death (5.2% vs. 3% p = 0.005) and MI (2.4% vs. 0.7% p = 0.001) at 3 years as compared with stent length<31.5 mm.15 Moreno et al documented the correlation between ST and stent length in a previous meta-analysis.16
R-ZES has better biocompatibility, drug-release kinetics and anti restenotic efficacy compared to previously introduced Zotarolimus Eluting Stent (ZES).17,18 R-ZES and EES has shown similar safety and efficacy during a follow up of 4-years in the Resolute All Comers trial.19 In our study, R-ZES in a cohort of patients with significant ischemia and at least one long lesion requiring stenting, showed favorable clinical and angiographic results during a follow up of one year. Among 110 lesions with a mean length of 24.67 ± 4.87 mm and mean vessel diameter of 2.85 ± 0.32 mm, one-year rate of TLF was 6.36% and binary restenosis was 7.5%.
Our study is unique compared to the similar studies of long lesions because of the high prevalence of Diabetes mellitus. Patients in trial, with high prevalence of risk factors and varied clinical presentations represent those who are usually referred for PCI in this part of the world. However these observations should be confirmed in a trial with large number of similar patients with longer term of follow up. Another notable finding in our cohort was the small vessel size. Mean RVD of the whole cohort was 2.84 ± 0.32 mm while in the diabetic patients it was only 2.4 ± 0.43 mm. Small vessels and long lesions still remain to be a challenge even in the DES era. Promising results with new generation Platinum Chromium Everolimus Eluting Stent with low rate of TLF has been observed in this group of patients in a recent study.20 With increasing number of diabetic patients being considered for PCI in our population, interventional strategy for small vessels with long and diffuse disease will be the focus of further study.
7. Conclusion
Implantation of R-ZES to treat long coronary artery lesions in a group of real-world patients with multiple risk factors and varied clinical presentations has been found to be safe and efficacious. The Device success was 100% and 1-year MACE rate of death, MI, TLR was low with no incidence of ST. The binary restenosis and angiographic in-stent late lumen loss was consistent with previous results.
8. Limitations
This is a single centre study with relatively short-term follow-up of 12 months. The number is small to make any sub group analysis. Even though we planned for 100% angiographic follow up, we were able to achieve only 84%. However we consider this reasonable in the light of the fact that similar studies quote around 70% follow up angiograms.
Conflicts of interest
All authors have none to declare.
Acknowledgment
The authors acknowledge the contributions of Dr. Muhammed Shaffi, Dr. Remya Rajesh, Mr. Jinbert Lordson, Mr. Binoj Mohan and Ms. Girija Devi for the co-ordination of the study and their help in the preparation of this manuscript. Medtronic India Pvt. Ltd. supported the 9 month angiography for all patients.
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