Incidence and predictors of restenosis after sirolimus-eluting stent implantation in high-risk patients

Interventional Cardiology

Incidence and predictors of restenosis after sirolimus-eluting stent implantation in high-risk patients Alberto Berenguer, MD,a Vicente Mainar, MD,a Pascual Bordes, MD,a Jose Valencia, MD,a Silvia Go ´ mez, BS,a and Teresa Lozano, MDb Alicante and Villajoyosa, Spain

Background Sirolimus-eluting stents (SESs) have not been evaluated systematically in clinical scenarios or with the vascular morphologies associated with the highest rates of restenosis. Methods

Between May 2002 and August 2003, 1379 percutaneous interventions were carried out at our center, 231 with SES implantation in patients with complex coronary lesions: (1) left main trunk, (2) bifurcations, (3) long lesions, (4) calcified lesions, (5) proximal segment of the left anterior descending coronary, (6) restenotic lesions, (7) total occlusions, (8) ostial lesions, and (9) vessels b 2.75 mm. Angiographic follow-up was carried out in the 6th month in 201 patients. Clinical, angiographic, and procedural variables were analyzed to assess predictors of restenosis.

Results Of the patients, 42.6% were diabetic and 20.2% were insulin dependent. A total of 263 lesions was treated. Mean lesion length was 16.5 F 11 mm and mean vessel diameter was 2.54 F 0.7 mm. A total of 327 stents was implanted to fully cover the entire lesion, in most cases after predilatation (89.1%). The mean segment length covered by the stent was 26 F 12 mm and the stent length/lesion length ratio was 1.7 F 0.9. Binary restenosis was found in 8.7%, but there was no edge restenosis. The only predictors of restenosis were female sex (OR 3.44, 95% CI 1.31-8.99, P = .011) and lesion length N30 mm (OR 3.39, 95% CI 1.07-10.77, P = .038). Conclusions

In scenarios that usually entail high restenotic risk in patients with conventional stent implantation, SESs had a low incidence of restenosis without edge complications. (Am Heart J 2005;150:536 - 42.)

The use of stents to treat coronary lesions has become increasingly accepted in recent years and has contributed to improving the results of percutaneous coronary revascularization.1,2 The restenosis phenomenon continues to be the main limitation to stent use,3-5 with rates of restenosis that can exceed 30% in certain subgroups such as individuals with diabetes6,7 and patients with long lesions, small vessels, or restenotic lesions.8,9 Attempts to reduce restenosis by improving stent design or administering systemic drugs have been fruitless.10 Recently, sustained local administration of anticoagulants, corticosteroids, and cytostatic drugs by means of the stent structure itself has been tried.11-13 The addition of cytostatic drugs has yielded promising results in the prevention of restenosis; thus, rapamycin From the aCardiology Service, General Hospital of Alicante, Spain, and bCardiology Section, Hospital Marina Baixa, Villajoyosa, Spain. Submitted May 27, 2004; accepted October 18, 2004. Reprint requests: Alberto Berenguer Jofresa, MD, Servicio de Cardiologı´a, Hospital General de Alicante, Avda. Maestro Alonso S/N, 03010 Alicante, Spain. E-mail: [email protected] 0002-8703/$ - see front matter n 2005, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2004.10.009

and paclitaxel have been shown to reduce the risk of restenosis in registries and clinical trials.13-21 The efficacy of sirolimus-eluting stents (SESs) in clinical scenarios and lesion morphologies associated with high rates of in-stent restenosis has not been studied systematically. Clinical variables such as diabetes mellitus and kidney failure and anatomical variables such as saphenous grafts, long lesions, small vessels, calcified lesions, bifurcations, ostial lesions, chronic occlusion, restenotic lesions, and left main trunk (LMT) lesions carry a high risk of restenosis.6-8 These conditions are not uncommon in the daily practice of hemodynamics laboratories and raise questions about their most suitable treatment, particularly when several conditions occur simultaneously or in patients with multivessel disease. In the present study, the incidence of restenosis and its predictors after SES implantation in complex lesions with a high risk of restenosis is analyzed.

Methods Study population At our center, from May 2002 to August 2003, percutaneous coronary revascularization procedures were performed on

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1379 patients. Of these, 231 patients with a total of 263 complex lesions in native coronary arteries and who demonstrated myocardial ischemia were treated by implantation of SESs (Cypher, Cordis, Johnson & Johnson Company) and were included in a prospective registry to analyze their clinical and angiographic evolution. Lesions had to satisfy at least one of the following conditions:

1. Significant stenosis of the LMT. 2. Bifurcation stenosis with a minimum lateral vessel diameter

3.

4.

5.

6. 7. 8. 9.

of 2 mm, with or without lateral branch involvement; the inclusion of cases with involvement of both branches was favored. Long stenoses measuring N18 mm and requiring treatment with 23-mm stents. Preference was given to diffuse or very long lesions requiring 33-mm stents or more than one stent. If the lesion length was N18 and b 23 mm, preference was given to concurrence with another unfavorable condition. Calcified lesions, including lesions treated previously by rotational atherectomy, cutting balloon, or conventional balloon angioplasty, when the case permitted. Stenosis of the proximal left anterior descending, preferably concurring with another unfavorable condition, specifically, ostial location, involvement of a developed diagonal branch, or complex irregular morphology. Restenotic lesions, either after previous balloon angioplasty or atherectomy or, preferably, in-stent restenosis. Subacute or chronic total occlusions that were passable, concurring with another unfavorable condition. Ostial lesions. Small-vessel stenosis (vessels of b 2.75 mm in diameter). In these cases, concurrence of another unfavorable circumstance.

Patients not included in the registry were those who presented with acute-phase myocardial infarction or cardiogenic shock, patients who had another condition that made clinical and angiographic follow-up difficult, and patients for whom the necessary stent size was unavailable, which was relatively frequent in main trunk lesions. No age restrictions were established. The inclusion of patients with unfavorable clinical characteristics, diabetes mellitus, chronic kidney failure, or multivessel disease was promoted. In this case, an attempt was made to treat all the lesions with SESs if the associated lesions met the conditions described. Patients with a high-risk clinical profile (insulindependent diabetes, chronic kidney failure, hemodialysis, poor ventricular function) were also included in the registry.

Procedure Sirolimus-eluting stent implantation. The stent positioning procedure was carried out according to routine laboratory practice. In general, lesions were predilated using balloons of the same size as the lesions being treated or smaller. Stent size selection was based on angiographic images. The use of stents covering the entire damaged segment from healthy segment to healthy segment was recommended in addition to generously sized stents or 2 or more stents, as needed, to ensure sufficient overlap and avoid gaps. Direct stenting was allowed. In some cases, the lesion was prepared with rotational

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atherectomy and then the entire damaged segment was covered with stents. Implantation was performed at high pressure, generally N12 atm. On certain cases such as that of long lesions and lesions of proximal segments, stents had to be postdilated after implantation to achieve good expansion. Balloons of up to 0.5 mm in diameter and not longer than the stent size chosen were used. Bifurcations. In bifurcations with preferred and/or exclusive involvement of the main vessel, a simplified procedure in which only the main vessel was treated was attempted; the secondary vessel was intervened only if there was significant deterioration. When both branches had to be treated, the bprovisional T-stentingQ technique was used; completion of the procedure with bkissing balloonQ postdilatation was recommended.

Concomitant treatment All patients received treatment with acetylsalicylic acid and clopidogrel. If a patient had not received a loading dose of 300 mg of clopidogrel, this dose was administered at the beginning of the procedure. Heparin was given at doses of 100 or 70 IU/kg if the patient received glycoprotein IIb/IIIa inhibitors. The use of glycoprotein IIb/IIIa inhibitors during the procedure was left to the discretion of the hemodynamics specialist. At release, patients were prescribed acetylsalicylic acid and clopidogrel 75 mg/d for 6 months.

Follow-up Angiographic follow-up 6 months postimplantation was proposed to all patients included in the registry. They were informed about the procedure and its objectives and informed consent was obtained from all patients who underwent reevaluation. Exact information was obtained on the clinical evolution of patients from months 1 to 6. After 180 F 12 days of follow-up, 4 patients died, 7 were lost to follow-up, and 18 refused follow-up catheterization. A total of 202 patients (87%) with a total of 230 lesions was reevaluated angiographically (88%).

Angiographic analysis Angiographic images were obtained in multiple projections after intracoronary nitroglycerin administration. For quantitative analysis, projections allowing optimal lesion definition were used. Images of the stent positioned at the target location were obtained before implantation to recognize the exact location in relation to certain reference points. This information was necessary to correctly establish stent location in follow-up angiography. Quantitative analysis was carried out by means of the MEDIS 5.2 automatic margin-detection system (Leiden, The Netherlands). The stent segment and proximal and distal 5-mm segments were analyzed with the Drug Eluting Stent Analysis-QCA software included in the MEDIS 5.2 system. Restenosis was considered binary when the angiographic stenosis at 6 months was N 50% in-stent or in the 5-mm segments proximal and distal to the stent.

Statistical analysis Continuous variables were expressed as mean F SD. Qualitative variables were expressed as percentages. To

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538 Berenguer et al

Table I. Clinical characteristics of 231 patients treated by SES implantation in complex lesions Age (y) Men Previous AMI Previous cerebrovascular accident Peripheral vascular disease Previous coronary surgery Kidney failure* Arterial hypertension Dyslipidemia Smoker Diabetes mellitus Non-insulin dependent Insulin dependent Stable angina FC I-II CCS FC III-IV CCS Acute coronary syndrome Unstable angina AMI without ST elevation AMI with ST elevation Silent ischemia Depressed ejection fraction(b 50%)

63 F 11 73.2 27.9 6.5 6.5 5.2 7.4 57.6 49.3 21.7 42.6 22.4 20.2 4.4 8.7 48.9 18.3 15.3 4.3 21.3

Values are expressed as percentages or mean F SD. AMI, Acute myocardial infarction. *Creatinine N1.4 g/dL.

Table II. Angiographic characteristics of the 263 lesions treated with SES implantation Vessel LAD RC CX LMT Other AHA classification A B1 B2 C Reference diameter (mm) Lesion length (mm) Occlusions Bifurcations Vessel b 2.75 mm Lesion N18 mm Lesion N30 mm Ostial lesions Calcified lesions Restenotic lesions

60.8 20 14 2.7 2.5 0 14 42 44 2.54 F 0.70 16.5 F 11 13 24.7 63.5 29.8 11.6 15.2 12.2 21.8

Values are expressed as percentages or mean F SD. RC, Right coronary artery; CX, circumflex artery.

Table III. Quantitative coronary analysis by segments

identify predictors of restenosis, univariate and multivariate analyses were made. In the univariate analysis, continuous variables were compared by means of the Student t test and qualitative variables were compared with the m2 test. Multivariate analysis was carried out by logistic regression analysis with progressive forward inclusion of variables that showed a P value of b.1 in univariate analysis. The area under the receiver operating characteristic curve of the predictive model was calculated.

Results Characteristics of patients and lesions The clinical characteristics of the patients are shown in Table I. Seventy-three percent (73.2%) were men and the mean age was 63 F 11 years. Among the classic risk factors, there was a high prevalence of diabetes mellitus (42.6%), especially insulin-dependent diabetes (20.2%). The characteristics of the lesions are summarized in Table II. The most frequently affected vessel was the left anterior descending (LAD) coronary (60.8%). Most of the lesions were type B2 or type C (86%) according to the American Heart Association (AHA) classification. The lesions included 63.5% small-vessel lesions, 36.1% proximal LAD, 25.6% bifurcation lesions, 29.8% N 18 mm and 11.6% N 33 mm, 21.8% restenotic lesions, 15.2% ostial lesions, 13% total occlusions, and 12.2% calcified lesions. The sum of these percentages is N100% because some lesions presented more than one unfavorable condition. On the average, each lesion presented 2.2 F 1

Proximal Minimum luminal diameter (mm) Before After 2.81 F 0.63 6 mos* 2.94 F 0.64 Stenosis (%) Before After 10 F 9 6 mos* 10 F 10 Late loss (mm)y 0.13 F 0.51 Restenosis N50% 0

Stent

Distal

0.68 F 0.36 2.52 F 0.44 2.38 F 0.66

2.33 F 0.56 2.48 F 0.60

73 F 13 12 F 5 22 F 15 0.15 F 0.58 (20) 8.7

11 F 9 12 F 10 0.13 F 0.51 0

Values are expressed as mean F SD or percentage. *Mean values obtained in the 230 lesions reevaluated. yDifference between the minimum luminal diameter postangioplasty and at 6 months.

unfavorable conditions. In 77.4% of the lesions, there were at least 2 unfavorable conditions.

Characteristics of procedure A total of 327 SESs was implanted satisfactorily, 1.25 F 0.43 stents per lesion. The mean implantation pressure was 16.7 F 2.4 atm and postdilatation was required in 68 lesions (29.3%). In 70 (26%) lesions, more than one stent, overlapped with each other, was needed to cover the entire length of the lesion. Twelve stents were implanted directly (4.7%), 9 after rotational atherectomy (3.5%), 7 after balloon cutting angioplasty (2.7%), and the rest (89.1%) after conventional balloon angioplasty.

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Table IV. Univariate analysis

Age (y) Women Previous AMI Previous cerebrovascular accident Peripheral vascular disease Previous coronary surgery Kidney failure Arterial hypertension Dyslipidemia Smoker Diabetes mellitus Non-insulin dependent Insulin dependent Stable angina Acute coronary syndrome Unstable angina AMI without ST elevation AMI with ST elevation Silent ischemia Vessel LAD RC CX LMT Other AHA classification B1 B2 C Reference diameter (mm) Lesion length (mm) Occlusions Bifurcations Vessel b2.75 mm Lesion N18 mm Lesion N30 mm Ostial lesions Calcified lesions Restenosis No. of unfavorable conditions Predilatation Postdilatation No. of stents implanted Total mean stent length (mm) Stent length/lesion length ratio

No restenosis (n = 210)

Restenosis (n = 20)

P*

63 F 11 22 28.6 7.7

64 F 13 50 45 0

NS .007 NS NS

9.2 8.7 7.7 56.8 47 22

15 10 20 80 65.8 10.5

NS NS .06 .04 NS NS

23 20 12

20 40 16.7

NS .039 NS

51.6 17.6 13.2 5.5

39 22.2 22.2 0

NS NS NS NS

61.2 17.2 14.8 3.3 3.3

55 35 10 0 0

NS NS NS NS NS

14.8 42 43.4 2.55 F 0.7 15 F 9 12.5 27 61 28 9 15 12 24 2.2 F 0.99

20 25 55 2.36 F 0.66 17 F 12 15 15 75 25 25 15 10 25 2.1 F 0.91

NS NS NS NS NS NS NS NS NS .03 NS NS NS NS

87 20 1.22 F 0.41 25 F 11

80 21 1.3 F 0.48 27 F 14

NS NS NS NS

1.7 F 0.8

2.1 F 1.5

NS

Clinical, angiographic, and procedure variables in relation to the presence of restenosis at 6 months. Values are expressed as percentages or mean F SD. *Values with P b .1 shown. NS, nonsignificant.

The mean length of the stent-covered segment was 26 F 12 mm, with a total-stent-to-lesion-length ratio of 1.7 F 0.9. Glycoprotein IIb/IIIa inhibitors were used in 35.2% of patients (23.3% abciximab, 11.9% tirofiban).

Table V. Characteristics of quantitative coronary angiography of the bin-lesion segmentQ in relation to the presence or absence of restenosis

Minimum luminal diameter (mm) Before After 6 mos Stenosis (%) Before After 6 mos Acute gain (mm) Late loss (mm)

No restenosis (n = 210)

Restenosis (n = 20)

P

0.69 F 0.37 2.53 F 0.45 2.49 F 0.53

0.66 F 0.36 2.34 F 0.37 1.20 F 0.57

NS .07 .001

72 13 62 1.69 1.14

NS NS .001 NS .001

73 12 18 1.83 0.046

F F F F F

13 5 9 0.48 0.46

F F F F F

13 5 10 0.5 0.67

Values are expressed as mean F SD or percentage. NS, nonsignificant ( P N .05).

Of the bifurcated lesions, 40 (61.6%) had no significant involvement of the lateral branch; a simplified procedure with stent in the main vessel without intervention in lateral branch was attempted without complications in all cases. Twenty-five (38.4%) were true bifurcations. A strategy of bprovisional T stentingQ was attempted, 5 lesions (20%) were treated by stenting the main vessel, 8 (32%) with stent in main vessel and balloon in lateral branch, and 12 (48%) with stent in both branches.

Quantitative coronary analysis The quantitative coronary analysis by segments is shown in Table III. Twenty restenoses occurred, representing 8.7% of the lesions reevaluated. All restenoses were in-stent. The mean length of the restenotic segment was 13.4 F 8.4 mm and the restenosis pattern was focal in 8 lesions (40%), multifocal in 7 (35%), and diffuse in 5 (25%). Predictors of restenosis Univariate analysis. The baseline characteristics of the patients who later developed restenosis or not are summarized in Tables IV and V. Among the clinical variables, the presence of restenosis at 6 months was associated with female sex (50% vs 22%, P = .007), chronic kidney failure (20% vs 7.7%, P = .06), arterial hypertension (80% vs 56.8%, P = .04), and insulin-dependent diabetes mellitus (40% vs 20%, P = .039). Among the angiographic variables, the subjects who developed restenosis had smaller vessels (2.36 F 0.66 vs 2.55 F 0.7 mm, P = NS) and longer lesions (17 F 12 vs 15 F 9 mm, P = NS) at baseline, but only the presence of lesions N30 mm (25% vs 9%, P = .03) and a smaller luminal diameter after angioplasty (2.34 F 0.37

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540 Berenguer et al

Figure 1

Percentage of binary restenosis in relation to sex and the presence of very long lesions (N30 mm).

vs 2.53 F 0.45, P = .08) was significantly related to the development of restenosis. Multivariate analysis. The variables that showed a P value of b.1 in univariate analysis were introduced in a logistic regression model with progressive forward inclusion of variables. The minimum luminal diameter postangioplasty was introduced as a qualitative variable depending on whether or not the value was higher or lower than the median. After multivariate adjustment, the only independent predictors of restenosis were female sex (OR = 3.44, 95% CI 1.31-8.99, P = .011) and lesion length N30 mm (OR = 3.39, 95% CI 1.07-10.77, P = .038). Chronic kidney failure showed a tendency to increase the risk of restenosis (OR = 3.31, 95% CI 0.9411.63, P = .06). The area under the receiver operating characteristic curve of this model was 0.7 95% CI (0.630.75). The presence of restenosis in relation to sex and lesion length is illustrated in Figure 1.

Clinical follow-up and adverse events Eighteen patients who refused a repeat catheterization had no adverse events. The 7 patients who were initially lost to follow-up at 6 months were relocated and contacted later. None of them had adverse events at 6 months either. In summary, information was obtained on the clinical evolution of all patients. Three patients died shortly after the procedure, 2 deaths were sudden and 1 was from a heart failure caused by an ST-elevation infarction in the territory of

the target vessel. One patient with poor LV function died at 5 months because of heart failure. Ten restenoses required repeated angioplasty. In 7 patients who were asymptomatic, revascularization was indicated for critical restenosis. In 2 patients with 3 lesions, a new angioplasty was indicated for severe symptoms, unstable angina in one and non-ST-elevation infarction in the other. Rapamycin-coated stents were implanted in all restenoses treated. Of the 65 patients with bifurcations, 58 (89.2%) had a repeated catheterization and only 3 restenoses occurred (5.2%). Two were located in the side branch where there was a stent. One was located in the main vessel requiring repeated angioplasty by severe symptoms. One patient with stents placed in both branches had a confirmed late thrombosis in relation to retrieval of clopidogrel and required repeated angioplasty. Except for these 2 repeated revascularizations, no other significant event at 6 months occurred in patients with bifurcations.

Discussion In the present study, which evaluated the characteristics of restenosis and its predictors after SES implantation in a selected group of patients who were highly representative of the more complex clinical and angiographic scenarios routinely seen in hemodynamic laboratories, there were 3 main findings: (1) despite the complexity of the patients and lesions treated, the frequency of angiographic restenosis at 6 months postimplantation was low; (2) there was no edge restenosis; and (3) the main predictors of restenosis in our patients were female sex and the presence of very long lesions. The first experiences in human beings with SESs14,15 and the RAVEL study16 showed the efficacy of these stents in reducing restenosis in favorable lesions. Since then, attention has centered on determining whether these results could be obtained in more complicated scenarios and if they could be maintained for more prolonged periods.22,23

Restenosis after SES implantation in complex lesions. Comparison with other studies The SIRIUS study of more complex coronary lesions encountered restenosis in 8.9%, fundamentally at the expense of edge restenosis in 5.7%.17 These good results stimulated interventionists to use stents in more complex scenarios; so, in recent months, observational studies of stenting of in-stent restenosis,24,25 bifurcations,26 unprotected LMT,27 and small vessels28 have appeared, with favorable results. However, few studies have been published in peer-reviewed journals analyzing the use of these stents in complex scenarios compared with a control group and including systematic angiographic follow-up. In the E-SIRIUS study20 of long lesions and small vessels, angiographic restenosis in patients

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with SESs occurred in 5.9%; the C-SIRIUS study21 obtained similar results, with a 2.3% occurrence of restenosis. In both studies, the restenosis rates of the control group treated with conventional stents were 42.3% and 52.3%, respectively, indicating the high restenotic potential of the treated lesions. In the present registry, angiographic restenosis was observed in 8.7%, a figure similar to the 8.9% seen in the SES group of the SIRIUS study. Although the present registry presented certain conditions such as a high proportion of diabetics and unfavorable vessel diameter and lesion length as well as the inclusion of lesions that were formally excluded from the SIRIUS study, the restenosis rates were comparable. The less favorable clinical and angiographic profile of our patients was probably compensated by the absence of edge restenosis. On the other hand, in the E-SIRIUS and C-SIRIUS studies, the rates of angiographic restenosis reported, 5.9% and 2.3%, respectively, were lower than the percentage found in our registry. This could be explained by the high proportion of diabetics in our group, which was much greater than in any published study of SESs. In addition, although E-SIRIUS and C-SIRIUS specifically analyzed small vessels and long lesions, the patients in our registry had longer lesions and smaller vessels. With respect to nonrandomized studies that have selectively analyzed scenarios of high restenosis risk with a similar design, the published results of the RESEARCH study29 indicate a rate of restenosis at follow-up of 7.9%. Considering the size of our population, the high rate of angiographic follow-up, and the similarity between our results and those of the RESEARCH study, we concluded that our study offers a reliable view of the potential of SESs in scenarios of high restenosis risk.

Edge restenosis after SES implantation The results of the SIRIUS study and observations by other authors suggest that restenosis after SES implantation is associated with insufficient lesion coverage and edge damage.30,31 Deployment techniques have been improved and the incidence of this phenomenon has decreased sharply, from 5.7% in the SIRIUS study17 to 3.4% in E-SIRIUS,20 2.3% in C-SIRIUS,21 1.6% in RESEARCH,29 and 0% in our registry. Predictors of restenosis after SES implantation The SIRIUS study was the first to analyze predictors of restenosis after SES implantation and reported that lesion length, vessel size, and diabetes mellitus are independent predictors of restenosis,17 as was already known for conventional stents. The RESEARCH study confirmed the same variables and included ostial location and in-stent restenosis (contributing factors), and left anterior descending location (preventive factor), as independent predictors of restenosis.29 In our registry, only very long

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lesions and female sex were associated independently with restenosis. Long lesion length coincides with the findings of the studies cited, which relate length with increased risk; however, the association with female sex has not been described before. Recent studies have demonstrated a greater risk of restenosis with conventional stents in women.8,32 In general, this risk has been related to the greater prevalence of risk factors32-34 and to the fact that women have smaller vessels,34 which means that the association described could be an epiphenomenon. Nonetheless, it is interesting in the light of our results to emphasize that differences in the potency of rapamycin in relation to sex have been reported. Ferron et al35 showed in different human lymphocyte proliferation assays that higher rapamycin concentrations were needed in women to achieve the same inhibition of lymphocyte proliferation as in men. Although our results do not allow definitive conclusions to be drawn regarding a greater incidence of restenosis after SES implantation in women and, much less, to attribute it to differences in the effect of rapamycin on the coronary arteries, the resulting hypotheses may merit exploration in new studies.

Conclusions In patients with a high risk of restenosis with conventional stents, the use of SESs has been shown to reduce the incidence of restenosis and prevent edge restenosis. More studies of specific scenarios such as lesions in bifurcations or the LMT are needed, using designs suitable for evaluating the true usefulness of SESs.

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