Advances in invasive evaluation and treatment of patients with ischemic heart disease

Advances in invasive evaluation and treatment of patients with ischemic heart disease

Hoeven, B.L. van der

Citation

Hoeven, B. L. van der. (2008, May 8). Advances in invasive evaluation and treatment of patients with ischemic heart disease. Retrieved from https://hdl.handle.net/1887/12862

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/12862

Note: To cite this publication please use the final published version (if applicable).

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Abstract

Aims

The effect of gender on the outcome of drug-eluting stents in patients with acute myocardial infarction is unknown. We report the gender-based outcome of the MISSION!

Intervention Study comparing sirolimus-eluting stents (SES) and bare-metal stents (BMS) in STEMI patients.

Methods and Results

157 Patients were treated with SES and 152 patients with BMS. The primary endpoint was in-segment late loss (LL) at 9 months. Secondary endpoints included clinical events at 30 days and 1 year. The in-segment LL in BMS women versus men and SES women versus men was 0.42±0.54mm versus 0.74±0.56mm (p=0.02) and -0.03±0.39mm versus 0.18±0.44mm (p=0.01). The rate of binary restenosis was 13.0% versus 24.8% (BMS group, p=1.00) and 2.9% versus 4.2% (SES group, p=0.23), respectively. The rate of negative in-segment LL (LL<0mm) was 21.7% versus 5.0% (BMS group, p=0.02) and 57.1% versus 31.6% (SES group, p=0.008), respectively. The rate of death, myocardial infarction, stent thrombosis, target vessel failure and target lesion revascularization was not different between women and men within the BMS and SES groups.

Conclusion

Women had a better 9 month angiographic outcome compared to men both after BMS and after SES implantation. However, this did not translate in differences in clinical events.

Female sex was an independent predictor of negative in-segment LL. (Current Controlled Trials number, ISRCTN62825862).

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CHAPTER 9

Gender differences after sirolimus- eluting or bare-metal stent

implantation for acute myocardial infarction: clinical and angiographic results of the MISSION! Intervention Study

Bas L. van der Hoeven, MD*, Su-San Liem, MD*, Jouke Dijkstra, PhD^†, Hein Putter, PhD^‡, Douwe E. Atsma, MD*, Marianne Bootsma, MD*, Katja Zeppenfeld, MD*, Pranobe V. Oemrawsingh, MD*, J. Wouter Jukema, MD*, Martin J. Schalij, MD*

* Department of Cardiology

† Department of Medical Statistics and Bio-Informatics

‡ Department of Radiology, Division of Image Processing Leiden University Medical Center, Leiden, The Netherlands

Submitted

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Introduction

Several studies demonstrated that women with acute myocardial infarction are at higher risk of short-term complications, including death, compared to men [1-5]. Stent implantation and the application of abciximab during primary PCI seem to reduce the risk of these early events in women [3,6,7]. Moreover, stent implantation during primary PCI improves long-term outcome by reducing the risk of restenosis and the need for target vessel revascularization compared to balloon angioplasty alone [8,9]. Although the short- term outcome of acute myocardial infarction is worse in women compared to men, several studies reported that women are at lower risk of developing restenosis after elective PCI with or without the use of stents [10-12]. Therefore, both the increased risk of short-term mortality and the lower risk of restenosis compared to men, may annihilate the beneficial effect of drug-eluting stents in women with acute myocardial infarction. Since there are no studies performed yet addressing the efficacy of drug-eluting stents in women with acute myocardial infarction, we report the gender-based outcome of the MISSION!

Intervention Study comparing sirolimus-eluting stents (SES) and bare-metal stents (BMS) in patients with ST-segment elevation myocardial infarction. The MISSION! Intervention Study showed that SES implantation in STEMI patients is associated with a favorable mid-term clinical and angiographic outcome compared to treatment with BMS.

Methods

Patient selection

The MISSION! Intervention Study was a single center, single blind, randomized controlled trial, comparing SES and BMS in patients with ST-segment elevation myocardial infarction.

The study complies with the Declaration of Helsinki and was approved by the Institutional Ethical Review Board. All patients gave informed consent before the procedure. An additional informed consent was obtained for follow-up angiography at 9 months. The current study is a sub-study comparing the 9 months angiographic results and 30 days and 12 months clinical outcome in women versus men. The study design, inclusion and exclusion criteria, endpoint definition and main outcomes of the study were published previously [13]. Briefly, patients were eligible for participation in the MISSION!

Intervention Study if they had symptoms of acute myocardial infarction which started less than 9 hours before arrival at the catheterization laboratory and the ECG demonstrated ST-segment elevation myocardial infarction (STEMI) defined as ST-segment elevation of

≥0.2mV in at least 2 contiguous leads in leads V1 through V3 and/or ≥0.1mV in other leads, or (presumed) new LBBB. Key exclusion criteria included age younger than 18 years or older than 80 years; the presence of a left main lesion of ≥50% stenosis; triple vessel disease, defined as ≥50% stenosis in three major epicardiac vessels; previous percutaneous coronary intervention or bypass grafting of the culprit vessel; failed thrombolytic therapy

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for the index infarction or reference diameter of the culprit lesion of less than 2.25mm or larger than 3.75mm. After successful positioning of the guidewire distally of the target lesion, randomization was performed in a 1:1 ratio to treatment with SES or BMS.

Endpoints

The primary endpoint was angiographic in-segment late loss (LL) at 9 months. Secondary endpoints included the composite of death, recurrent myocardial infarction or any revascularization procedure; cardiac death; recurrent myocardial infarction; target vessel revascularization; target lesion revascularization and target vessel failure (the composite of cardiac death attributable to the culprit vessel, recurrent myocardial infarction attributable to the culprit vessel and target vessel revascularization) and stent thrombosis. All events were adjudicated by a Clinical Event Committee whose members were blinded for the assigned treatment.

Study procedure

Before the procedure all patients received a loading dose of aspirin (300mg) and clopidogrel (300-600mg). At arrival in the hospital a bolus of abciximab (25µg/kg) was administered intravenously, followed by a 12 hours infusion of 10µg/kg/min. At start of the procedure a bolus of 5000U heparin was given.

Follow-up and data collection

Patients were seen at the out-patient clinic at 30 days, 3, 6, and 12 months. Aspirin (80- 100mg/day) was prescribed indefinitely and clopidogrel (75mg/day) for 12 months.

Patients were treated with beta-blocking agents, statins and ACE-inhibitors or ATII- blockers, according to current guidelines [14]. Follow-up angiography and IVUS imaging was performed at 9 months.

Quantitative coronary angiography (QCA) and IVUS analysis

Coronary angiograms obtained at baseline, after completion of the stenting procedure and at 9 months follow-up were digitally recorded and analyzed blinded for the assigned treatment. Analyses were performed with automated edge-detection software (CMS version 6.0, Medis Medical Imaging Systems, Leiden, The Netherlands) at the single worst view projection [15]. The contrast-filled non-tapered catheter tip was used for calibration. The stented zone and the in-segment zone (stent plus the proximal and distal 5mm stent edges) were evaluated. The reference diameter was determined by interpolation. For every segment, minimum luminal diameter (MLD), mean luminal diameter, percentage diameter stenosis, late luminal loss (LL) and the percentage binary restenosis were determined. LL was defined as the difference between the post- procedural and follow-up MLD. Negative LL was defined as a LL less than 0mm. The

Gender differences after SES or BMS implantation for acute myocardial infarction

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percentage diameter stenosis was defined as the difference between reference and actual diameter divided by the reference diameter and multiplied by 100. Binary restenosis was defined as more than 50% diameter stenosis within the in-segment zone. Since in-segment LL is determined by proximal edge LL, in-stent LL and distal edge LL, these parameters were put in a multivariate logistic regression analysis model to assess which of these were independent predictors of negative in-segment LL in both groups for women and men. The correlation between these determinants with negative in-segment LL was calculated.

Statistical analysis

Data are expressed as mean and standard deviation, except otherwise indicated.

Continuous variables were compared between the treatment groups with a t-test or, in case of non-normality, with the equivalent non-parametric test. Categorical variables were compared with Pearson’s χ2-test or Fisher’s Exact test. The angiographic outcome was adjusted by multivariate linear (late loss and percentage diameter stenosis) or logistic (binary restenosis, negative in-segment LL) regression analysis. The correlation between variables was calculated using Pearson’s method. All p values were two-sided, and a p value of less than 0.05 was considered statistically significant. All analyses were conducted with SPSS 12.0.1 statistical analysis software.

Results

Patient characteristics and procedural results

Of 310 patients included in the MISSION! Intervention Study, 152 were assigned to treatment with BMS and 158 to treatment with SES. In one male patient a SES could not be implanted and another stent was used. This patient was excluded for this sub-analysis.

Finally, 152 BMS patients and 157 SES were included in the analysis. In the BMS group 29 patients (19%) were women as compared to 40 women (25%) in the SES group (p=0.18).

Baseline clinical and angiographic characteristics and procedural characteristics are listed in Tables 1 and 2. Within the SES group, a family history of coronary artery disease was more common in women (62.5 vs. 40.2%, p=0.01). Moreover, the baseline reference diameter was smaller in women as compared to men (2.60±0.40 vs. 2.81±0.58, p=0.01).

There were no baseline clinical and angiographic differences between women and men in the BMS group. Procedural success rate was identical in the different groups (female and men, BMS and SES).

Angiographic outcome

Post-procedural and follow-up angiographic data were available in 124 BMS patients (82%) and 130 SES patients (83%). In the SES group 35 (27%) were women as compared to 23

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(19%) in the BMS group (p=0.11). The median duration of the angiographic follow-up was similar in women and men (both 272 days). There was no difference in time to angiographic follow-up between the BMS and SES group. There were no differences in baseline clinical and angiographic characteristics between the patients who did and who did not undergo follow-up angiography. Of the patients who did not undergo follow-up

Table 1. Baseline Clinical Characteristics

Characteristic Women Men p value Number

BMS SES

29 40

123 117 Age - yrs

BMS SES

62.6±11.1 59.8±13.9

58.3±11.6 59.0±10.2

0.07 0.76 Hypertension - No (%)

BMS SES

8 (27.6) 11 (27.5)

31 (25.2) 37 (31.6)

0.79 0.63 Current smoker - No (%)

BMS SES

17 (58.6) 20 (50.0)

68 (55.3) 63 (53.8)

0.75 0.67 Hyperlipidemia - No (%)

BMS SES

5 (17.2) 8 (20.0)

20 (16.3) 29 (24.8)

1.00 0.54 Family history of CAD - No (%)

BMS SES

13 (44.8) 25 (62.5)

47 (38.2) 47(40.2)

0.51 0.01 Diabetes mellitus - No (%)

BMS SES

2 (6.9) 7 (17.5)

8 (6.5) 13 (11.1)

1.00 0.30 Prior myocardial infarction - No (%)

BMS SES

0 (0.0) 0 (0.0)

5 (4.1) 7 (6.0)

0.58 0.19 Prior PCI or CABG - No (%)

BMS SES

0 (0.0) 0 (0.0)

2 (1.6) 5 (4.3)

1.00 0.33 Symptoms onset to first ECG - min.

BMS SES

Symptoms onset to balloon inflation - min.

BMS SES

87 (61–153) 125 (65–193)

172 (145–263) 206 (156–274)

107 (72–151)^† 85 (45–142)

195 (156–256)^‡ 175 (128–247)

0.67 0.10

0.57 0.13 Maximum creatininphosphokinase - U/l

BMS SES

1931 (767–2567) 1685 (1063–3239)

2210 (1035–4335) 1928 (769–3555)

0.09 0.79 BMS vs. SES: † P=0.02; ‡ P=0.04

Gender differences after SES or BMS implantation for acute myocardial infarction

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Characteristic Women Men p value Target vessel - No (%)

BMS LAD RCA / LCX SES

LAD RCA / LCX

13 (44.8) 13 (44.8)^‡ / 3 (10.4)

24 (60.0) 7 (17.5) / 9 (22.5)

17 (56.9) 38 (30.9) / 15 (12.2)

63 (53.8) 33 (28.2) / 21 (18.0)

0.38

0.39 Multivessel disease - No (%)

BMS SES

6 (20.7) 13 (32.5)

44 (35.8) 43 (36.8)

0.12 0.63 Baseline flow - No (%)

BMS: TIMI 0-1 / 2-3 SES: TIMI 0-1 / 2-3

20 (69.0) / 9 (31.0) 29 (72.5) / 11 (27.5)

85 (69.1) / 38 (30.9) 84 (71.8) / 33 (28.2)

0.99 0.93 Baseline reference diameter - mm

BMS SES

2.91±0.49^† 2.60±0.40

2.92±0.59 2.81±0.58

0.91 0.01 Minimal luminal diameter - mm

BMS SES

0.22±0.34 0.20±0.27

0.28±0.42 0.21±0.38

0.53 0.88 Diameter stenosis - mm

BMS SES

92.7±10.7 92.6±13.0

90.6±14.2 91.9±10.8

0.47 0.75 No. of stents in the culprit lesion

BMS SES

1.38±0.62 1.33±0.69

1.38±0.63 1.34±0.58

0.98 0.88 Implanted stent length - mm

BMS SES

24.9±12.0 24.4±14.1

26.8±10.8 27.2±12.3

0.40 0.23 Maximum stent diameter - mm

BMS SES

3.38±0.26^† 3.24±0.29

3.36±0.25 3.33±0.24

0.74 0.10 Maximum balloon diameter - mm

BMS SES

3.41±0.30 3.29±0.30

3.40±0.30 3.39±0.30

0.85 0.08 Maximal balloon pressure – atm

BMS SES

11.7±3.6 12.0±2.9

12.3±2.8 12.5±2.3

0.31 0.31 Maximal balloon to artery ratio

BMS SES

1.16±0.19 1.22±0.15

1.14±0.19 1.15±0.18

0.59 0.05 Abciximab therapy - No (%)

BMS SES

29 (100.0) 40 (100.0)

122 (99.2) 117 (100.0)

1.00 1.00 Flow after the procedure - No (%)

BMS: TIMI 0-2 / 3 SES: TIMI 0-2 / 3

3 (10.3) / 26 (89.7) 2 (5.0) / 38 (95.0)

8 (6.5) / 115 (93.5) 10 (8.5) / 107 (91.5)

0.44 0.73 Procedural success - No (%)

BMS SES

26 (89.7) 38 (95.0)

114 (92.7) 107 (91.5)

0.70 0.73 BMS vs. SES: ‡ p=0.04, † p=0.01

Characteristic Women Men p value Target vessel - No (%)

BMS LAD RCA / LCX SES

LAD RCA / LCX

13 (44.8) 13 (44.8)^‡ / 3 (10.4)

24 (60.0) 7 (17.5) / 9 (22.5)

17 (56.9) 38 (30.9) / 15 (12.2)

63 (53.8) 33 (28.2) / 21 (18.0)

0.38

0.39 Multivessel disease - No (%)

BMS SES

6 (20.7) 13 (32.5)

44 (35.8) 43 (36.8)

0.12 0.63 Baseline flow - No (%)

BMS: TIMI 0-1 / 2-3 SES: TIMI 0-1 / 2-3

20 (69.0) / 9 (31.0) 29 (72.5) / 11 (27.5)

85 (69.1) / 38 (30.9) 84 (71.8) / 33 (28.2)

0.99 0.93 Baseline reference diameter - mm

BMS SES

2.91±0.49^† 2.60±0.40

2.92±0.59 2.81±0.58

0.91 0.01 Minimal luminal diameter - mm

BMS SES

0.22±0.34 0.20±0.27

0.28±0.42 0.21±0.38

0.53 0.88 Diameter stenosis - mm

BMS SES

92.7±10.7 92.6±13.0

90.6±14.2 91.9±10.8

0.47 0.75 No. of stents in the culprit lesion

BMS SES

1.38±0.62 1.33±0.69

1.38±0.63 1.34±0.58

0.98 0.88 Implanted stent length - mm

BMS SES

24.9±12.0 24.4±14.1

26.8±10.8 27.2±12.3

0.40 0.23 Maximum stent diameter - mm

BMS SES

3.38±0.26^† 3.24±0.29

3.36±0.25 3.33±0.24

0.74 0.10 Maximum balloon diameter - mm

BMS SES

3.41±0.30 3.29±0.30

3.40±0.30 3.39±0.30

0.85 0.08 Maximal balloon pressure – atm

BMS SES

11.7±3.6 12.0±2.9

12.3±2.8 12.5±2.3

0.31 0.31 Maximal balloon to artery ratio

BMS SES

1.16±0.19 1.22±0.15

1.14±0.19 1.15±0.18

0.59 0.05 Abciximab therapy - No (%)

BMS SES

29 (100.0) 40 (100.0)

122 (99.2) 117 (100.0)

1.00 1.00 Flow after the procedure - No (%)

BMS: TIMI 0-2 / 3 SES: TIMI 0-2 / 3

3 (10.3) / 26 (89.7) 2 (5.0) / 38 (95.0)

8 (6.5) / 115 (93.5) 10 (8.5) / 107 (91.5)

0.44 0.73 Procedural success - No (%)

BMS SES

26 (89.7) 38 (95.0)

114 (92.7) 107 (91.5)

0.70 0.73 BMS vs. SES: ‡ p=0.04, † p=0.01

Table 2. Baseline Angiographic and Procedural Characteristics

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angiography, 6 died within 12 months (4 BMS (1 woman) vs. 2 SES (0 women)) and 4 experienced stent thrombosis within 30 days for which target lesion revascularization was performed in 2 patients (1 BMS vs. 1 SES).

BMS versus SES

Table 3 shows quantitative coronary angiographic results of post-procedural and follow-up angiograms. Comparing the outcome of the BMS and the SES group, the amount of in- segment late loss was higher in the BMS group for both sexes (mean difference: women 0.45mm (95%CI 0.20–0.70mm); men 0.56mm (95%CI 0.42–0.70mm)). The percentage diameter stenosis at 9 months was also higher in the BMS group (mean difference: women 12.7% (95%CI 6.3–19.2%); men 16.7% (95%CI 12.4–21.1%)). After adjustment for age, diabetes mellitus, target vessel, stented segment length, post-procedural MLD, post- procedural reference diameter and post-procedural percentage diameter stenosis, both late loss and percentage diameter stenosis at 9 months remained significantly higher in the BMS group for both women and men as compared to the SES women and men. Binary restenosis occurred more often in men in the BMS group compared to men in the SES group (RR 5.94 (95%CI 2.15–16.44), p<0.001). Of interest, in women, there was no statistically significant difference in the binary restenosis rate between both stent groups (RR 4.57 (95%CI 0.51–41.3), p=0.29). In men, this difference remained significant after adjustment for assigned stent type, age, diabetes mellitus, target vessel, stented segment length, post-procedural MLD, post-procedural reference diameter and post-procedural percentage diameter stenosis. In women the difference remained non-significant after correction for these variables.

Women versus men

Comparing the outcome in women and men within the BMS and SES groups, the angiographic results in women were significantly better than in men at 9 months in both study groups with regard to in-segment late loss (mean difference: BMS 0.32mm, (95%CI 0.06–0.57mm); SES 0.21mm (95%CI 0.05–0.38mm), Figure 1) and percentage diameter stenosis (mean difference: BMS 10.0% (95%CI 2.2–17.9%); SES 6.0% (95%CI 1.1–10.9%)).

After adjustment for age, diabetes mellitus, target vessel, stented segment length, post- procedural MLD, post-procedural reference diameter and post-procedural percentage diameter stenosis, female sex remained an independent negative predictor for these outcome parameters in both the BMS and SES group. The binary restenosis rate did not differ between women and men in both the BMS and SES group, even after adjustment for age, diabetes mellitus, target vessel, stented segment length, post-procedural MLD, post- procedural reference diameter and post-procedural percentage diameter stenosis.

Gender differences after SES or BMS implantation for acute myocardial infarction

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SESBMS SES vs. BMS

Characteristic Women Men p value Women Men p value Women p value Men p value Number 35 95 23 101 Stented segment length - mm20.9±10.2 22.8±10.00.34 22.2±10.3 22.8±8.00.76 0.65 0.96 Reference diameter - mmPost-procedure Follow-up Post-procedure – follow-up 2.71±0.41 2.77±0.42 -0.06±0.34 3.03±0.50 3.03±0.500.00±0.26 0.001 0.006 0.25 3.00±0.41 2.91±0.34 0.09±0.33 3.03±0.55 2.93±0.54 0.11±0.35 0.78 0.84 0.79 0.10 0.19 0.097 0.99 0.17 0.01 Mean in-segment diameter - mmPost-procedure Follow-up Post-procedure – follow-up 2.82±0.35 2.74±0.41 0.08±0.17 3.06±0.372.94±0.420.12±0.16 0.001 0.02 0.22 3.02±0.32 2.55±0.36 0.47±0.32 3.01±0.40 2.44±0.480.58±0.34 0.99 0.27 0.15 0.03 0.08 <0.001 0.41 <0.001 <0.001 In-segment MLD - mmPost-procedure Follow-up In-segment LL Negative in-segment LL - No (%) 2.18±0.42 2.21±0.44 -0.03±0.39 20 (57.1) 2.44±0.512.26±0.59 0.18±0.44 30 (31.6) 0.009 0.64 0.01 0.008 2.37±0.47 1.96±0.44 0.42±0.54 5 (21.7) 2.42±0.53 1.69±0.69 0.74±0.56 5 (5.0) 0.69 0.05 0.02 0.02 0.11 0.04 0.001 0.008 0.82 <0.001 <0.001 <0.001 In-stent MLD - mmPost-procedure Follow-up In-stent LL Negative in-stent LL - No (%) 2.49±0.32 2.35±0.43 0.14±0.22 9 (25.7) 2.74±0.39 2.53±0.54 0.21±0.4323 (24.2) 0.001 0.08 0.37 0.86 2.68±0.32 1.96±0.44 0.72±0.45 0 (0.0) 2.72±0.38 1.72±0.61 1.00±0.56 0 (0.0) 0.65 0.08 0.03 1.00 0.03 0.002 <0.001 0.008 0.78 <0.001 <0.001 <0.001 Proximal edge MLD - mmPost-procedure Follow-up Proximal edge LL Negative proximal edge LL - No (%) 2.70±0.41 2.48±0.52 0.22±0.36 8 (24.2) 2.89±0.562.70±0.590.20±0.3323 (28.0) 0.08 0.07 0.76 0.68 3.00±0.59 2.68±0.53 0.32±0.40 6 (28.6) 2.93±0.58 2.58±0.64 0.35±0.50 19 (22.6) 0.64 0.52 0.78 0.57 0.03 0.19 0.34 0.72 0.65 0.23 0.02 0.42 Distal edge MLD - mmPost-procedure Follow-up Distal edge LL Negative distal edge LL - No (%) 2.13±0.41 2.18±0.44 -0.05±0.32 21 (60.0) 2.45±0.552.39±0.610.06±0.3138 (41.8) 0.002 0.06 0.08 0.07 2.38±0.51 2.37±0.40 0.01±0.41 10 (47.6) 2.41±0.58 2.21±0.63 0.19±0.45 33 (34.4) 0.81 0.30 0.09 0.25 0.05 0.12 0.54 0.37 0.63 0.06 0.02 0.30 In-segment diameter stenosis (%) Post-procedure Follow-up Binary restenosis - No (%) 19.6±7.8 19.9±10.8 1 (2.9) 19.9±8.3 25.9±13.1 4 (4.2) 0.84 0.02 1.00 21.1±9.1 32.6±13.6 3 (13.0) 20.2±9.242.7±17.8 25 (24.8) 0.68 0.01 0.23 0.49 0.001 0.29 0.79 <0.001 <0.001

LL = late loss; MLD = minimum luminal diameter

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Negative late loss

In both women and men, negative in-segment LL was more often observed in the SES group (Table 3). However in both stent groups, negative in-segment LL occurred more often in women as compared to men. In the BMS group negative in-segment late loss in women was not related to the change in the reference diameter (R=-0.31, p=0.15) or change in the mean in-segment diameter (R=-0.28, p=0.19) during the follow-up period. In BMS men negative in-segment late loss was related to the change in mean in-segment diameter (R=-0.23; p=0.02) but not to the change in reference diameter (R=-0.18, p=0.08).

In the SES group negative in-segment late loss in both women and men was related to the change in mean in-segment diameter (women: R=-0.49, P=0.003; men: R=-0.25, p=0.02) and the change in reference diameter (women: R=-0.61, P<0.001; men: R=-0.48, p<0.001).

Using multivariate logistic regression analysis it was analyzed whether in-segment LL was determined independently by in-stent LL, proximal edge LL or distal edge LL for BMS and SES women and men. There were no independent determinants of negative in-segment LL in the BMS group for both women and men. In the SES women group distal edge LL was the only independent determinant of negative in-segment LL (p=0.008). In the SES men group this were in-stent LL (p=0.04) and distal edge LL (p=0.008). After multivariate logistic regression analysis including the variables assigned stent type, age, sex, diabetes mellitus,

0 10 20 30 40 50 60 70 80 90 100

-1,5 -1,0 -0,5 0,0 0,5 1,0 1,5 2,0 2,5 3,0 Late luminal loss (mm)

Percentile

BMS Men LL BMS Women LL DES Men LL DES Women LL Figure 1.

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target vessel, stented segment length, post-procedural MLD, post-procedural reference diameter and post-procedural percentage diameter stenosis, female sex was an independent predictor of negative in-segment late loss at 9 months (OR 3.85, 95%CI 1.78- 8.32; p=0.001).

Clinical outcome

As listed in Table 4, there were no differences between the BMS group and SES group for women and men during the first 30 days after the index procedure. Within the BMS and SES groups there were no differences between women and men. After 1 year there were no differences in the rate of death, myocardial infarction or stent thrombosis between the BMS and SES group for women and men. The rates of target lesion revascularization and target vessel failure were significantly higher in the BMS group for both women and men.

Within the BMS or SES group there were no statistically significant differences in clinical event rate between women and men, including target vessel failure and target lesion revascularization (Figure 2, Panel A and B).

CHAPTER 9

SES BMS SES vs. BMS Characteristic Women Men p value Women Men p value Women

p value Men p value

Number 40 117 29 123

30 days - % Any cardiac event Cardiac death

Recurrent myocardial infarction Spontaneous

Procedure related Target vessel failure Target vessel revascularization Target lesion revascularization Stent thrombosis

2.5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

6.8 1.7 2.6 1.7 0.9 5.1 1.7 0.9 1.7

0.31 0.41 0.30 0.40 0.56 0.15 0.40 0.56 0.41

13.8 0.0 3.4 3.4 0.0 3.4 0.0 0.0 3.4

4.1 0.8 0.8 0.0 0.8 2.4 1.6 0.8 0.8

0.05 0.63 0.27 0.40 0.63 0.77 0.49 0.63 0.27

0.08 --- 0.24 0.24 --- 0.24

--- --- 024

0.34 0.53 0.29 0.14 0.97 0.27 0.95 0.97 0.29 12 months - %

Any cardiac event Cardiac death

Recurrent myocardial infarction Spontaneous

Procedure related Target vessel failure Target vessel revascularization Target lesion revascularization Stent thrombosis

10.0 0.0 0.0 0.0 0.0 2.5 2.5 0.0 0.0

15.4 1.7 7.9 1.7 6.1 8.6 5.3 3.5 1.7

0.39 0.41 0.07 0.40 0.11 0.20 0.47 0.23 0.40

24.1 3.4 6.9 3.4 3.4 17.2 14.3 10.7 3.4

25.6 0.8 10.0

1.7 8.3 15.0 14.2 11.7 1.7

0.97 0.27 0.64 0.38 0.40 0.72 0.98 0.90 0.38

0.12 0.24 0.09 0.24 0.52 0.03 0.07 0.04 0.24

0.08 0.53 0.60 0.95 0.39 0.15 0.02 0.02 0.95

Table 4. Clinical outcome at 30 Days and 12 Months

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Discussion

Key findings of this sub-analysis of the MISSION! Intervention Study comparing BMS and SES in STEMI patients, were: 1) the amount of in-segment LL was lower in women compared to men in both the BMS and the SES group; and 2) in both women and men SES implantation resulted in a lower amount of in-segment LL compared to BMS implantation. However these angiographic differences did not translate in differences in clinical outcome since event rates were comparable between women and men. 3) Female sex was an additional independent predictor of negative in-segment LL in both the BMS and SES groups.

Gender differences after SES or BMS implantation for acute myocardial infarction

0 50 100 150 200 250 300 350

Men Women 70

80 90 100

p=0.90 89.3%

88.3%

Time (days after the index procedure)

TLR free survival (%)

A.

Figure 2.

0 50 100 150 200 250 300 350

0

Men Women 70

80 90 100

P=0.18

100.0%

95.6%

Time (days after the index procedure)

TLR free survival (%)

B.

Kaplan–Meier estimates of survival free from target lesion revascularisation among patients treated with BMS (Panel A) and those treated with SES (Panel B).

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However, negative in-segment LL was more frequently observed after SES implantation than after BMS implantation. In both women and men negative in-segment LL was mainly determined by distal edge LL and significantly correlated with the change in reference diameter and mean diameter during the follow-up period.

The results of this study are in line with the results of other studies comparing the outcome between women and men after elective PCI. Several studies demonstrated that the risk of angiographic restenosis and target vessel failure is lower in women as compared to men [10,12], although others did report no difference in outcome [16] or a worse outcome [17]. These different outcomes may be related to gender-based discrepancies in study participation and interpretation of symptoms or non-invasive functional tests to detect ischemia resulting in differences in referral for follow-up angiography and target lesion revascularization. However, as far as we know, no evidence is currently available about gender differences after primary PCI with drug-eluting stents.

One study reported gender-based outcome after paclitaxel-eluting stent implantation during elective PCI [18]. In that study, no angiographic and clinical differences between women and men in the BMS and paclitaxel-eluting stent group were found. There are no studies published about the differences between women and men after SES implantation d uring either elective or primary PCI.

Although there was a significant difference in angiographic outcome between women and men, this did not translate in a different clinical outcome. Most likely caused by the relative small number of patients (especially women) included in the study However, since LL is an important parameter to evaluate the efficacy of stents for the prevention of restenosis, it is tempting to speculate that a larger study will also demonstrate significant differences in clinical outcome between women and men [19].

In this study the local effects of SES implantation in women and men in lesions causing acute myocardial infarction were evaluated. Different effects can be expected in women and men since female gender is associated with different plaque characteristics compared to men [20,21]. For example, it is known that intracoronary thrombosis in women (especially young women) is relatively more frequently related to eroded plaques, while in men intracoronary thrombosis is mainly associated with ruptured plaques. Differences in plaque constitution, and possibly also in thrombus burden or constitution, may have consequences for the effects of drug-eluting stents on restenosis and vessel geometry.

Moreover, the hormonal milieu of women may protect against restenosis because of the higher levels of circulating estrogens [22,23]. Estrogen positively influences endothelial function and recovery, which may result in faster re-endothelialization and less neointimal growth [24,25].

In this study it was demonstrated that female sex was an independent predictor of negative in-segment LL after BMS or SES implantation. Although negative in-segment LL could not be correlated to angiographic parameters after BMS implantation, after SES

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implantation it was correlated with the change in reference diameter and mean in- segment diameter during follow-up. Moreover, after SES implantation negative in-segment LL was mainly determined by distal edge LL in both women and men, indicating that the long-term angiographic outcome of SES in acute myocardial infarction is mainly determined by the segment distally of the stent. Negative in-segment LL may be due to resolvement of spasm during the follow-up period, but effects of the released drug on the vessel wall may also account for this phenomenon. Intravascular ultrasound studies are needed to unravel the local effects of sirolimus-eluting stents in acute myocardial infarction patients.

Limitations

This study was not designed to reveal a gender difference of stent implantation in patients with acute myocardial infarction. Furthermore patients were not stratified by gender during the randomization process. Therefore, selection bias might have influenced the result. Moreover, especially the number of patients in the women BMS and SES groups were low, which has consequences for the power and reproducibility of our results. The results of this study can therefore not be translated into daily practice. However, the results indicate, as many other studies in elective PCI patients did, that results achieved in men cannot be extrapolated to women and that women should preferably be considered as a separate group.

Conclusions

Women had a better 9 month angiographic outcome compared to men both after BMS and after SES implantation during STEMI. However, this did not translate in differences in clinical events. Female sex was found to be an independent predictor of negative in- segment LL. Of interest negative in-segment LL was mainly determined by the distal edge LL after SES implantation in both women and men.

Acknowledgment

Clinical Events Committee: A.V.G. Bruschke, MD, Leiden, The Netherlands and S.A.I.P.

Trines, MD, Leiden University Medical Center, Leiden, The Netherlands.

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Gender differences after SES or BMS implantation for acute myocardial infarction