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

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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

Background

Diabetes mellitus (DM) is a strong predictor for in-stent restenosis. This may be due to a higher level of vascular inflammation. We hypothesized that diabetic patients will benefit from dexamethasone-eluting stents, since local inflammation and consequently neointimal growth is suppressed and no systemic side effects will occur.

Methods

21 Consecutive patients with DM with 32 lesions were treated with dexamethasone-eluting stents. Excluded were patients with triple vessel disease, bifurcation lesions, previous revascularization of the culprit vessel, reference diameter smaller than 2.5mm or larger than 3.75mm. MACE (death, myocardial infarction, revascularization) was counted at 12 months. At 6 months, angiographic follow-up was performed.

Results

Of the patients, 38% had insulin dependent DM. Lesion type was type A/B1 56% and B2/C in 44%. Lesion length was 15.7±8.4mm and the reference diameter 2.83±0.53mm. Event free survival at 12 months was 62%. Any revascularization procedure was performed in 33%

and target lesion revascularization in 24% of the patients. At 6 months in-stent late loss was 1.07±0.64mm. Binary restenosis occurred in 28.1% of the lesions. The event free survival in insulin dependent DM was worse compared to non-insulin dependent DM (92.1 vs 37.8%; p<0.01). Insulin dependent diabetic patients had higher in-stent late loss compared to non-insulin dependent diabetic patients (1.44±0.83 vs. 0.83±0.51mm;

p<0.01).

Conclusion

Treatment with dexamethasone-eluting stents in patients with DM is associated with a relatively high restenosis rate. Our data suggest a differential effect of dexamethasone- eluting stents in insulin dependent compared to non-insulin dependent DM.

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CHAPTER 4

Dexamethasone-eluting stents for the prevention of in-stent

restenosis: evidence for a differential effect in insulin dependent and non-insulin dependent diabetic patients

B.L. van der Hoeven, MD*, N.M.M. Pires, MD*^,‡, H.M.

Warda, MD*, H. Putter, MSc^†, P.H.A. Quax, MSc^‡, M.J.

Schalij, MD*, J.W. Jukema, MD*

*Department of Cardiology, Leiden University Medical Center

† Department of Medical Statistics and Bio-Informatics, Leiden University Medical Center

‡TNO-Quality of Life, Gaubius Laboratory Leiden, The Netherlands

Int J Cardiol 2008; 124: 166-71

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Introduction

Patients with diabetes mellitus are a challenging population for the interventional cardiologist. Despite the introduction of intracoronary stents, restenosis in these patients occurs more frequently compared to non-diabetic patients [1]. These discrepant results are due to differences in the anatomical and metabolic milieu caused by the diabetes [2,3]. In this process, hyperglycemia plays a central role. Hyperglycemia is associated with the development of cardiovascular complications and cardiovascular events in diabetic patients. Advanced glycation endproducts (AGEs) seem to play an important role in this process. These AGEs impair endothelial function, stimulate subendothelial proliferation and amplify vascular inflammation. This results in more neointima formation after coronary stent implantation [4].

Since the introduction of drug-eluting stents, restenosis rates have further declined, even in patients with diabetes mellitus [5,6]. However, target lesion revascularization rates in diabetic patients are still higher after implantation of drug-eluting stents compared to non-diabetic patients. Therefore, since diabetic patients remain a challenging population, we evaluated the efficacy of dexamethasone-eluting stents in these patients.

Dexamethasone is a potent anti-inflammatory and immunosuppressive drug, inhibiting proliferation of fibroblast, smooth muscle cells and macrophages [7]. These are pivotal processes in the development of restenosis. Indeed, systemic application of immunosuppressive drugs resulted in a lower restenosis rates in non-diabetic patients8.

However, systemic dexamethasone may cause serious long-term side effects, especially in patients with diabetes, since it disturbs glucose and lipid metabolism. Local application with a drug-eluting stents seems therefore a good alternative in these patients, which was the focus of our investigation.

Methods

Patients

Consecutive patients with diabetes mellitus referred for elective percutaneous intervention were eligible. Patients were eligible if they were 18 to 85 years old and had received a diagnosis of stable or unstable angina or silent ischemia. Additional eligibility criteria were non-ostial stenosis with a lesion length ≤20mm in a native coronary artery with a reference diameter that permitted implantation of 2.75-3.50mm stents without involvement of significant side branches (diameter 2.0mm). Patients with recent (<2 weeks) myocardial infarction (MI), chronic total occlusion, disease with 50 percent or more stenosis in three major epicardiac vessels, left main stenosis of 50 percent or more, previous Percutaneous Coronary Intervention (PCI) or Coronary Artery Bypass Grafting (CABG), renal insufficiency, and/or contraindications for combined antiplatelet therapy

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with clopidogrel, acetylsalicylic acid and abciximab were excluded. The study was approved by our Institutional Review Board. All patients gave informed consent.

Study Procedures

Lesions were treated with the use of standard interventional techniques. Predilatation was not required. In this study, dexamethasone eluting stents were used (Dexamet, Abbott Vascular Devices Ltd). Stent size and length were selected based on visual estimation and periprocedural Quantitative Coronary Angiography. After the stent had been implanted additional dilatation was performed to ensure that there was less than 30 percent residual stenosis without angiographic evidence of dissections. If additional short stents were needed due to dissections or incomplete coverage of the lesion, short bare-metal stents were allowed, since dexamethasone eluting stents were only available in the length of 18 or 22mm. All patients received 5000U of heparin at start of the procedure and acetylsalicylic acid plus 300mg loading dose of clopidogrel 48 hours before the procedure, followed by 75mg/d of clopidogrel for 6 months and 80mg/d of acetylsalicylic acid indefinitely. Before the procedure all patients were treated with an abciximab bolus of 0.25μg/kg, followed by a peri-procedural abciximab infusion of 12.5μg/kg/min with a maximum of 10μg/kg/min for 12 hours. Three angiograms in 2 orthogonal projections were obtained in each patient: before intervention, immediately after the intervention, and at 6-month follow-up. Intravascular Ultrasound (IVUS) was performed with the Volcano system, which allows digital storage of pullback sequences. Automated pullbacks at 0.5mm/s were performed after stenting and at 6 months follow-up from a distal side branch to the coronary ostium. Each angiogram or ultrasound sequence was preceded by 200 to 300 µg of intracoronary nitroglycerin.

Follow-up

Patients were followed 12 months after stent implantation. At 6 months after the index procedure follow-up angiography and IVUS was performed as part of our clinical treatment protocol. All major adverse cardiac events, defined as death, myocardial infarction and additional revascularization procedures were recorded. Revascularization procedures during follow-up angiography were performed if the patient had symptoms of angina and/or a functional study like a cycle test or myocardial perfusion scintigraphy indicated ischemia.

Quantative Coronary Angiographic and Ultrasound Evaluation

Quantitative Coronary Analyses were performed by an experienced operator, independent of the clinical outcome and blinded for the IVUS findings with the use of automated edge- detection techniques (QCA-CMS 6.0, Medis, Leiden). Before and after the procedure and at 6 months follow-up the luminal diameter and degree of stenosis were measured within the Dexamethasone-eluting stents for the prevention of in-stent restenosis in diabetic patients

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stented zone and within the in-segment zone, defined as the stented segment plus the 5mm proximal and distal of the stented segment. Acute gain was defined as the difference between the post- and pre-procedural luminal diameters. Late loss was defined as the difference between the follow-up and post-procedural luminal diameters. Binary restenosis was defined as 50 percent or more diameter narrowing of the luminal diameter after the procedure.

Quantitative Coronary Ultrasound analyses were performed by an experienced operator, independent of the clinical and angiographic outcome. An automated contour detection program (QCU-CMS version 4.1, Medis, Leiden) was used to identify all lumen and stent areas in all frames within the target segment (the stented segment plus 5mm proximal and distal of the stent or a major side branch within 5mm of the stent edge). Restenosis was defined as 50 percent of more lumen area narrowing compared to the reference area as defined by the interpolation of a proximal and distal reference area, within 10mm outside the proximal and distal stent edge. Volume neointima hyperplasia and plaque burden were calculated by an automated 3-dimensional reconstruction of the stent and proximal and distal edge segments applying Simpson’s rule to cross-sectional area data of multiple IVUS images acquired with a fixed distance between the images.

Statistical Analysis

Results are expressed as means plus or minus standard deviation or as proportions (%).

Comparisons of continuous variables between insulin and non-insulin dependent diabetic patients were done with the independent sample T-test. Survival without the composite of major adverse cardiac events during follow-up was analyzed by Kaplan-Meier methods.

Comparison of event-free survival between non-insulin and insulin dependent diabetic patients was made with the Wilcoxon log ranks test. Differences were considered statistically significant when the p value was <0.05.

Results

From June 2003 to June 2004, 21 diabetic patients were eligible for treatment with the dexamethasone eluting stent. Of these patients, 8 (38%) had insulin dependent diabetes.

Mean age was 65.9±8.9 years and 67% were men. Other risk factors like dyslipidemia, hypertension, smoking and positive family history of coronary artery disease were, as expected in these patients, frequently present. Patient characteristics are described in Table 1. Five (24%) patients had a previous myocardial infarction. Multiple vessel disease, defined as a 50% percent stenosis or previously treated coronary artery was present in 58%

of the patients. In these 21 patients, 32 de novo coronary lesions were treated with one or more dexamethasone eluting stents. In two patients an additional short bare-metal stent was used to cover a dissection. The target vessel was the left anterior descending artery

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and ramus circumflex in 31% and the right coronary artery in 38% of the lesions. Lesion class, according to the American College of Cardiology – American Heart Association classification, was type A in 6%, B1 in 50%, B2 in 22% and C in 22% of the lesions. There were no statistically significant differences in the baseline characteristics as listed in Table 1 between patients with or without insulin dependent diabetes mellitus.

Adverse Events

Major adverse cardiac events are listed in Table 2. During hospitalization one patient experienced an acute myocardial infarction due to thrombus formation within the culprit vessel. During the follow-up period, no patients died or had a myocardial infarction.

Additional revascularization procedures were needed in 38% of the patients. In 10% of the patients a non-target lesion was revascularized during the follow-up period. Target lesion revascularization rate at 12 months occurred in 5 (24%) patients and 7 lesions (21% of all lesions). Kaplan-Meier estimates of event-free survival are shown in Figure 1. Patients with insulin dependent diabetes mellitus had a significantly worse event-free survival

Age - yrs 65.9±8.3

Male sex - % 67

Previous myocardial infarction - % 24 Insulin dependent diabetes mellitus - % 38

Hypercholesterolaemia - % 67

Hypertension - % 71

Current smoker - % 14

Family history of CAD - % 43

Unstable angina (%) 24

Vessels diseased or previously treated - % 1

2

42 58 Target vessel - %

RCA LAD RCX

38 31 31 Lesion type - %

A B1 B2 C

6 50 22 22 Reference diameter – mm 2.83±0.53

Lesion length - mm 15.7±8.44

CAD = coronary artery disease

Table 1. Patient and lesion characteristics

Dexamethasone-eluting stents for the prevention of in-stent restenosis in diabetic patients

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compared to non-insulin dependent diabetics (p=0.01). The patients with non-insulin dependent diabetes had a high event free survival of 92.4 percent at 12 months.

Table 2. Major cardiac events during hospitalization and 12 months follow-up No. of lesions

(n=32)

No. of patients (n=21) During index hospitalization

Death

Myocardial infarction

Target lesion revascularization Target vessel revascularization Non-target vessel revascularization

0 1 0 0 0

0 1 0 0 0 After discharge

Death

Myocardial infarction

Target lesion revascularization Target vessel revascularization Non-target vessel revascularization

0 0 7 1 2

0 0 5 1 2

Total 11 8

Cumulative event-free survival - % -- 62

Proximal edge Stented segment Distal edge Mean diameter - mm

Before procedure After procedure At follow-up

3.00±0.79 3.07±0.65 2.96±0.87

2.26±0.49 3.04±0.36 2.42±0.44

2.60±0.51 2.52±0.51 2.55±0.57 Minimal luminal diameter - mm

2.71±0.71 2.84±0.66 2.68±0.80

0.99±0.50 2.60±0.38 1.51±0.68

2.31±0.56 2.24±0.52 2.28±0.57 Stenosis - % of luminal diameter

10.9±13.1 12.0±11.1 12.2±9.8

64.0±14.7 13.9±9.7 47.4±22.6

13.9±11.5 19.5±12.6 16.7±12.0

Acute gain - mm 0.15±0.40 1.59±0.47 -0.05±0.33

Late loss - mm 0.12±0.52 1.07±0.64 0.09±0.48

Binary restenosis - % of lesions 0 28.1 0

Table 3. Results of Quantitative Angiographic Analyses

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Quantitative Coronary Analysis

Angiographic follow-up was performed in 18 of 21 patients. Angiographic data at six months were available for 27 out of 32 lesions. Baseline reference diameter was 2.83mm with an average lesion length of 15.7mm. Mean in-stent late loss at 6 months was 1.07mm. Binary restenosis occurred in 9 (28.1%) lesions. The type of restenosis was diffuse in all patients according to the classification of Mehran. Pattern II (diffuse intrastent) restenosis occurred in 4 patients and pattern III (diffuse proliferative) in 5 patients.

Although baseline angiographic data were not completely comparable between patients with insulin dependent diabetes and non-insulin dependent diabetes, it is striking that insulin dependent diabetics had higher in-stent late loss at 6 months compared to non- insulin dependent diabetics, 1.44 vs. 0.83mm (Table 5). Moreover, insulin dependent diabetic patients had a higher average percentage in-stent stenosis at 6 months, 59.6 vs.

39.1 percent respectively (p<0.05).

0 100 200 300 400

Days after index procedure 0,0

0,2 0,4 0,6 0,8 1,0

Event-free Survival (Fraction of patients)

NIDDM

IDDM

Figure 1. Kaplan-Meier estimates of survival without death, myocardial infarction or target lesion revascularization in patients with insulin dependent (IDDM) versus non- insulin dependent diabetes mellitus (NIDDM).

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Quantitative Intravascular Ultrasound Analysis

At 6 months follow-up, intravascular ultrasound was performed in 20 lesions. The IVUS probe could not be passed in 6 lesions due to severe in-stent restenosis, especially in insulin dependent diabetic patients. Therefore, no formal QCU comparison could be made between the non-insulin and insulin dependent groups. For the whole group the results of quantitative intravascular ultrasound analyses are described in Table 4. Percent neointimal volume at 6 months was 24%.

Table 4. Stented segment results of Quantitative Angiographic Analyses in patients with insulin dependent (IDDM) versus non-insulin dependent diabetes mellitus (NIDDM)

IDDM (n=11) NIDDM (n=16)

Stented segment length - mm 28.8±11.1 22.8±9.7 NS Pre-intervention

Minimal luminal diameter - mm Mean luminal diameter - mm

0.70±0.33 1.84±0.30

1.19±0.51 2.52±0.38

p<0.05 p<0.05 Post-intervention

Minimal luminal diameter - mm Mean luminal diameter - mm Reference diameter - mm Acute gain - mm

2.44±0.38 2.83±0.33 2.77±0.45 1.73±0.40

2.72±0.34 3.20±0.31 3.10±0.42 1.48±0.50

p=0.053 p<0.05 p<0.05 NS Follow-up

Minimal luminal diameter - mm Mean luminal diameter - mm Late loss - mm

Diameter stenosis - %

1.00±0.74 2.04±0.28 1.44±0.83 59.6±28.7

1.90±0.36 2.61±0.37 0.83±0.51 39.1±12.3

p<0.01 p<0.01 p<0.05 p<0.05 NIDDM = non-insulin dependent diabetes mellitus

IDDM = insulin dependent diabetes mellitus

Mean stent area - mm² 9.00±3.33

Mean luminal area - mm² 6.83±2.64 Minimal stent area - mm² 7.29±2.09 Minimal luminal area - mm² 4.53±1.32 Follow-up area stenosis - % 45.9±11.6

Stent volume - mm³ 210±122

Lumen volume - mm³ 160±99

Neointimal volume - mm³ 50±30

Percent neointimal volume - % 24±9

Table 5. Results of Quantitative IVUS Analyses at 6 months (n=20 lesions)

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Discussion

This study demonstrated that dexamethasone-eluting stents in diabetic patients with stable lesions have a binary restenosis rate of 28%. Target lesion revascularization rate occurred in 24% of the patients during the 12 months follow-up period, mean late loss at 6 months is 1.07mm and the percentage neointimal volume at 6 months is at least 24%. The binary restenosis rate after implantation of paclitaxel- or sirolimus-eluting stents in diabetics wvith comparable lesions was 6.4% and 17.6%, respectively [5,6]. Mean late loss in these studies was 0.17mm in the TAXUS study and 0.40mm in the SIRIUS study. The results achieved with the dexamethasone-eluting stents seem therefore to be less favorable than results achieved with paclitaxel- or sirolimus-eluting stents and comparable to bare-metal stents. This is in accordance with a recently published study, comparing neointimal volume in humans at six months with intravascular ultrasound between bare- metal, sirolimus-, paclitaxel- and dexamethasone-eluting stents [9]. Dexamethasone- eluting stents seem therefore no good alternative for paclitaxel- or sirolimus- eluting stents in patients with diabetes mellitus.

A remarkable finding in this cohort is the significant difference in target lesion revascularization rate and event-free survival between patients with insulin dependent and non-insulin dependent diabetes mellitus. Patients with insulin dependent diabetes mellitus had a target lesion revascularization rate of 63% compared to 0% in the non- insulin dependent diabetic patients. In-stent late loss was also higher in the insulin dependent group. In part, these differences are probably due to the fact that the lesions in insulin dependent diabetic patients had a lower reference diameter and had a smaller post-intervention minimal luminal diameter. These factors are considered independent predictors of in-stent restenosis and can explain the worse outcome in the insulin dependent diabetic patients [10]. Another explanation could also be that the insulin dependent diabetic patients had a longer duration of diabetes, a worse glycaemic control or more severe atherosclerosis, factors which are associated with a worse outcome.

Nevertheless, the high event-free survival in the non-insulin dependent diabetic patients in combination with a high event rate in the insulin dependent diabetic patients raises the question whether insulin therapy is associated with a different outcome after drug-eluting stent implantation. This may be due to differences in baseline characteristics, such as the duration of the diabetes mellitus or worse glycaemic control in the insulin-dependent patients. Moreover, it may be due to an adverse effect of insulin therapy in combination with dexamethasone. From other studies we know that insulin dependent diabetic patients can respond differently on drug-eluting stent therapy compared to non-insulin dependent diabetic patients. Within the SIRIUS study insulin dependent diabetic patients had a 13.2% target lesion revascularization rate compared to 4.3% in non-insulin dependent diabetic patients6. In-lesion late loss was 0.59mm and 0.35mm, respectively.

This in contrast with the TAXUS study, using paclitaxel, in which no difference in efficacy in insulin dependent compared to non-insulin dependent diabetic patients was found (7.9%

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and 6.2% target lesion revascularization and 0.14mm and 0.19mm in-lesion late loss). This indicates that insulin dependence is possibly associated with a worse local or systemic milieu with different effects of various drugs. Therefore careful and extensive investigation of potential drug-eluting stents is needed to evaluate their efficacy and safety and insulin dependent and non-insulin dependent diabetic patients should possibly be considered as separate groups. However, when we look at the in-stent late loss of 0.83mm in the non-insulin dependent group in this study, it is still much higher compared to the results of TAXUS and SIRIUS. Thus, it can be expected that dexamethasone-eluting stents will be associated with a relatively high rate of in-stent restenosis in a larger patient cohort.

A major limitation of this study is the small number of patients. Moreover, it is not a randomized comparison with an uncoated stent or coated stent with another drug.

Therefore, definite conclusions cannot be drawn. However, a small study with angiographic and echographic follow-up, can give an idea in the efficacy of drug-eluting stents in the absence of clinical trials, while limiting the costs. Moreover, IVUS results comparing insulin and non-insulin diabetic patients are not reliable since the IVUS probe could not pass the lesion at 6 months follow-up in a significant number of lesions, all in insulin dependent patients. Finally, the intention of this study was not the comparison between non-insulin dependent versus insulin dependent diabetic patients. This analysis was performed retrospectively. Differences in outcome between these groups may therefore be influenced by selection bias.

In conclusion, implantation of dexamethasone-eluting stents in patients with diabetes mellitus is associated with a relatively high restenosis rate and seems therefore no good alternative for paclitaxel- or sirolimus-eluting stents implantation. Moreover, our data suggest a differential effect of dexamethasone-eluting stents in insulin-dependent compared to non-insulin diabetic patients which warrants further clinical evaluation.

Acknowledgement

JWJ is an established clinical investigator of the Netherlands Heart Foundation (grant 2001D032).

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