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J Am Coll Cardiol, 2005; 45:1172-1179, doi:10.1016/j.jacc.2004.10.075
© 2005 by the American College of Cardiology Foundation
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FOCUS ISSUE: DRUG-ELUTING STENTS: TAXUS-IV

Outcomes with the polymer-based paclitaxel-eluting TAXUS stent in patients with diabetes mellitus

The TAXUS-IV trial

James B. Hermiller, MD, FACC*,1, Albert Raizner, MD, FACC{dagger}, Louis Cannon, MD, FACC{ddagger}, Paul A. Gurbel, MD, FACC§, Michael A. Kutcher, MD, FACC||, S. Chiu Wong, MD, FACC, Mary E. Russell, MD#,2, Stephen G. Ellis, MD, FACC**,1, Roxana Mehran, MD, FACC{dagger}{dagger}, Gregg W. Stone, MD, FACC{dagger}{dagger},1,* TAXUS-IV Investigators

* St. Vincent’s Hospital, Indianapolis, Indiana
{dagger} Cardiac Cath Lab Research Center, Houston, Texas
{ddagger} St. Mary’s Medical Center, Saginaw, Michigan
§ Sinai Hospital of Baltimore, Baltimore, Maryland
|| Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina
New York Presbyterian Hospital, New York, New York
# Boston Scientific Corp., Natick, Massachusetts
** Cleveland Clinic Foundation, Cleveland, Ohio
{dagger}{dagger} Columbia University Medical Center and the Cardiovascular Research Foundation, New York, New York

Manuscript received June 28, 2004; revised manuscript received October 18, 2004, accepted October 19, 2004.

* Reprint requests and correspondence: Dr. Gregg W. Stone, Cardiovascular Research Foundation, 55 East 59th Street, 6th Floor, New York, New York 10022. (Email: gstone{at}crf.org).


   Abstract
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Methods
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 Discussion
 References
 
OBJECTIVES: We sought to determine the safety and efficacy of polymer-regulated site-specific delivery of paclitaxel in patients with diabetes mellitus undergoing stent implantation.

BACKGROUND: Percutaneous coronary intervention in patients with diabetes is associated with high rates of restenosis and repeat revascularization due to excessive neointimal proliferation, a process that may be blunted with the site-specific delivery of paclitaxel.

METHODS: In the TAXUS-IV trial, 1,314 patients were prospectively randomized to the slow rate-release polymer-based paclitaxel-eluting TAXUS stent or the bare-metal EXPRESS stent (Boston Scientific Corp., Natick, Massachusetts). Medically treated diabetes was present in 318 patients (24%), 105 of whom required insulin.

RESULTS: Among patients with diabetes, the TAXUS stent, compared to the bare-metal stent, reduced the rate of 9-month binary angiographic restenosis by 81% (6.4% vs. 34.5%, p < 0.0001), and reduced the 12-month rates of target lesion revascularization by 65% (7.4% vs. 20.9%, p = 0.0008), target vessel revascularization by 53% (11.3% vs. 24%, p < 0.004), and composite major adverse cardiac events by 44% (15.6% vs. 27.7%, p = 0.01). The one-year rates of cardiac death (1.9% vs. 2.5%), myocardial infarction (3.2% vs. 6.4%), and subacute thrombosis (0.6% vs. 1.2%) were comparable between the paclitaxel-eluting and control stents, respectively. In the insulin-requiring subgroup, the TAXUS stent reduced angiographic restenosis by 82% (7.7% vs. 42.9%, p = 0.0065), and reduced the one-year rate of target lesion revascularization by 68% (6.2% vs. 19.4%, p = 0.07), a relative reduction similar to patients without diabetes.

CONCLUSIONS: The site-specific delivery of paclitaxel after coronary stent implantation is highly effective in reducing clinical and angiographic restenosis in patients with diabetes mellitus.

Abbreviations and Acronyms
  MACE = major adverse cardiac events
  MI = myocardial infarction
  TLR = target lesion revascularization
  TVR = target vessel revascularization

As many as 25% of percutaneous coronary interventions involve diabetic patients (1). Compared with non-diabetics, the prognosis in patients with diabetes after balloon angioplasty is poor, with a high rate of restenosis and late target vessel occlusion (2,3). Although coronary stenting significantly attenuates restenosis and target vessel revascularization (TVR) rates in the diabetic patient compared to balloon angioplasty alone, the frequency and severity of in-stent restenosis remains greater than in non-diabetics and is often recalcitrant, frequently requiring bypass grafting for symptomatic relief (4–8).

The polymer-regulated delivery of both paclitaxel and sirolimus at the site of arterial injury has been shown to reduce clinical and angiographic restenosis rates after stent implantation in de novo coronary lesions in a broad range of patients (9–11). Less is known about the outcomes of these devices in patients with diabetes. The hypothesis of the present study was that the site-specific delivery of paclitaxel would lower angiographic restenosis rates and improve intermediate-term clinical outcomes in medically treated diabetic patients in the TAXUS-IV trial.


   Methods
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Results
 Discussion
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Patient population and protocol.   The TAXUS-IV study design has been previously described (11). Patients with single de novo lesions with visually estimated lesion length between 10 to 28 mm and reference vessel diameter 2.5 to 3.75 mm coverable by a single study stent were eligible for randomization. Major exclusion criteria have been reported previously (11). Of the 1,314 patients enrolled, 318 (24.2%) had diabetes (defined as being treated with oral hypoglycemic agents or insulin at the time of admission); of these, 213 (67.0% of the diabetics and 16.2% of the entire population) received oral diabetic medications only, and 105 (33.0% of the diabetics and 8.2% of the entire population) were insulin-requiring.

Patients were randomized to either the slow rate-release, polymer-based, paclitaxel-eluting EXPRESS stent (the TAXUS stent, Boston Scientific Corp., Natick, Massachusetts) or an identical appearing bare-metal EXPRESS stent. Randomization was stratified by the presence of medically treated diabetes and vessel size (<3.0 or ≥3.0 mm). Stents were available in diameters of 2.5, 3.0, and 3.5 mm and in lengths of 16, 24, and 32 mm. After mandatory pre-dilatation, an appropriate-sized stent (stent to distal reference vessel diameter ratio of 1 to 1.1:1 and approximately 4 to 6 mm longer than the lesion) was implanted at ≥12 atm. Aspirin was administered to all patients before the procedure and indefinitely thereafter. Unfractionated heparin was administered per standard practice, and glycoprotein IIb/IIIa inhibitor use was at operator discretion. Clopidogrel was recommended as a 300-mg loading dose before catheterization and then was administered at 75 mg/day for at least six months. Clinical follow-up was scheduled at one, four, and nine months, and yearly thereafter for five years. Angiographic follow-up at nine months was performed in a subset of 559 patients, including 136 patients with diabetes, 47 of whom were among the insulin-requiring subgroup.

Data management, end points, and definitions.   All case report forms were verified by independent study monitors on-site. The primary end point was the incidence of TVR for ischemia. Major adverse cardiac events (MACE) were defined as cardiac death, myocardial infarction (MI), or ischemia-driven TVR. Target vessel failure was defined as death, MI, or ischemia-driven revascularization related to the target vessel. Clinical end points were adjudicated by an independent committee blinded to treatment allocation after review of original source documentation. The definitions for the end points and the methodology for their ascertainment have been previously reported (11). Angiographic core laboratory analysis was performed as previously described and blinded to clinical outcomes (11).

Statistical methods.   Subset analysis of patients with diabetes was pre-specified in the study protocol. Categorical variables were compared by the Fisher exact test. Continuous variables are presented as mean ± 1 SD or median with interquartile ranges and were compared by the Wilcoxon two-sample test. Survival estimates were created and displayed as Kaplan-Meier curves, and compared using the log-rank test. The influence of baseline variables on the nine-month rates of angiographic restenosis in patients with diabetes was evaluated with logistic regression, using entry and stay criteria of <0.20 and <0.10, respectively. In addition to randomization arm, the following baseline clinical, angiographic, and procedural variables were entered into the multivariate model: age, gender, current cigarette use, hypertension, hyperlipidemia, prior MI, unstable angina, creatinine clearance, left ventricular ejection fraction, epicardial vessel, lesion length, reference vessel diameter, baseline minimal luminal diameter, stent length, maximum inflation pressure, ostial location, tortuosity, angulation, calcification, and study stents implanted (yes vs. no).


   Results
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Discussion
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Baseline characteristics.   As seen in Table 1, patients with medically treated diabetes compared to those without diabetes were more often female, more commonly had hypertension and hyperlipidemia, and had lower baseline left ventricular ejection fraction. Lesion length was also significantly greater and reference vessel diameter significantly smaller in patients with diabetes.


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  		Table 1. Selected Baseline Demographic and Angiographic Features of Pooled Patients With and Without Diabetes Mellitus
 
Among patients with diabetes, the baseline demographic and angiographic features were similar in the paclitaxel-eluting and bare-metal stent groups, except that there were slightly more patients with hyperlipidemia in the drug-eluting stent group (Table 2). Procedural parameters and outcomes including number, mean length and diameter of stents utilized, use of glycoprotein IIb/IIIa inhibitors, and final minimal luminal diameter and percent diameter stenosis were also similar (Table 3). Among patients without diabetes, all baseline features, as well as procedural parameters and results, were similar in the paclitaxel-eluting and control stent arms.


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  		Table 2. Baseline Demographic and Angiographic Features in the Randomized Groups Stratified by the Presence of Diabetes
 

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  		Table 3. Procedural Outcomes in Patients Stratified by the Presence of Diabetes Mellitus
 
Clinical outcomes.   Among diabetics, the paclitaxel-eluting stent in comparison to the control bare-metal stent reduced the one-year rates of target lesion revascularization (TLR) by 65% and TVR by 53%, due to reductions in both the need for repeat percutaneous intervention and bypass graft surgery (Table 4). As a result, MACE rates were reduced by 44%; the rates of death, MI, and stent thrombosis were similar between control and TAXUS stent. The relative reductions in TLR and TVR were similar in non-diabetic patients (Table 4).


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  		Table 4. Clinical Outcomes Through 12 Months Stratified by Diabetes
 
Angiographic results.   Pre-specified follow-up angiography at nine months was completed in 136 of 189 patients with diabetes, and in 423 of 543 patients without diabetes (72.0% vs. 77.9%, respectively, p = 0.54). In the diabetic subgroup, the paclitaxel-eluting stent reduced late loss and late loss index compared to the control stent, resulting in a greater late minimal lumen diameter and lower diameter stenosis (Table 5). As a result, binary restenosis in patients with diabetes was reduced by 84% within the stent (relative risk 0.16 [0.06 to 0.45], p < 0.0001) and by 81% over the analysis segment (0.19 [0.07 to 0.47], p < 0.0001). The paclitaxel-eluting stent also markedly reduced the frequency of diffuse in-stent restenosis in patients with diabetes, such that when restenosis did occur, the lesions were significantly shorter. The relative reduction in restenosis seen with the paclitaxel-eluting stent in diabetic patients was comparable to non-diabetics (Table 5). Among patients with diabetes mellitus, the most powerful determinate by logistic regression analysis of freedom from analysis segment restenosis was randomization to the TAXUS stent rather than a bare-metal stent (odds ratio [95% confidence interval 0.06 to 0.34], p < 0.0001).


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  		Table 5. Angiographic Measures at Nine Months Stratified by the Presence of Diabetes
 
Impact of type of diabetic treatment.   In pooled analysis, the one-year rate of MACE progressively increased from patients without diabetes, to those managed with oral medications, to those requiring insulin (13.4% vs. 19.6% vs. 26.2%, respectively, p = 0.0003). The paclitaxel-eluting stent reduced the one-year rates of MACE, target vessel failure, TLR, and TVR to a similar degree in diabetic patients requiring insulin, those managed with oral agents alone, and those without diabetes (Fig. 1). Similarly, in patients treated with the control stent, angiographic restenosis rates (analysis segment) tended to be higher in insulin-requiring diabetics compared to diabetic patients managed with oral medications and non-diabetics (42.9% vs. 29.7% vs. 24.4%, respectively, p = 0.17). Restenosis was significantly reduced in all three groups with the paclitaxel-eluting stent (Fig. 2) such that the rate of restenosis was similar and independent of diabetic status or treatment type (7.7% vs. 5.8% vs. 8.5%, respectively, p = 0.81). Among patients treated with the paclitaxel-eluting stent, the late loss and loss index were similar or lower among insulin-requiring diabetics compared with those managed on oral medications alone (Table 6).



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  		Figure 1 One-year clinical outcomes among patients randomized to the paclitaxel-eluting TAXUS stent versus a control EXPRESS stent, stratified by diabetic status and treatment type. (Upper left graph) Composite major adverse cardiac events. (Upper right graph) Target vessel failure. (Lower left graph) Target vessel revascularization. (Lower right graph) Target lesion revascularization.

 


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  		Figure 2 Nine-month rates of binary restenosis among patients randomized to the paclitaxel-eluting TAXUS stent versus a control EXPRESS stent, stratified by diabetic status and treatment type. (Left) In-stent restenosis. (Right) Analysis segment restenosis. Black bars = control; open bars = TAXUS.

 

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  		Table 6. Angiographic Outcomes in the Diabetic Subgroup According to Diabetic Treatment
 

   Discussion
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 Results
 Discussion
References
 
Previous studies of percutaneous intervention in diabetic patients have consistently demonstrated an independent association of diabetes with adverse outcomes, including greater rates of MACE, TLR and TVR, and restenosis (5–8,11–15). The smaller vessel size, longer lesion length, and greater plaque burden present in the diabetic patient may contribute to increased restenosis after stent implantation. In addition, acute results are often less optimal in the diabetic, with less acute gain (16). The inferior acute gains may be due to greater plaque burden (16) or mediated, in part, by vascular noncompliance. Moreover, neointimal hyperplasia is increased in the diabetic artery after coronary intervention, resulting in greater late in-stent lumen loss (17). It has been postulated that the hyperglycemic state may induce, alter, or accentuate the biologic mechanisms that contribute to the greater tissue proliferation and more diffuse restenotic pattern seen with diabetes. Specifically, vascular tissue thickening may be related to glycosylation of vascular collagen and elastin (18,19). Regardless of the mechanisms, the presence of diabetes (especially insulin-requiring diabetes) has been a consistent, independent predictor of restenosis in nearly all previous stent trials.

In the present analysis of 318 diabetic patients in the TAXUS-IV randomized trial, representing the largest reported experience to date with drug-eluting stents in diabetics, the paclitaxel-eluting stent substantially reduced late lumen loss, late loss index, and restenosis compared with the control bare-metal stent. As a result, TAXUS stent implantation resulted in significantly lower rates of TLR and TVR in diabetics, with a reduction in the need for both repeat percutaneous coronary intervention and bypass surgery. The relative and absolute magnitude of the benefit of the paclitaxel-eluting stent in patients with diabetes was comparable to that in non-diabetics. Notably, luminal dimensions at follow-up were greater with site-specific paclitaxel treatment both within the stent and at the proximal and distal edges. Moreover, diffuse in-stent restenosis was reduced in diabetic patients by more than 90% with the paclitaxel-eluting stent, such that when angiographic restenosis did occur, it was predominantly focal in nature.

Importantly, the relative efficacy of the TAXUS stent in insulin-requiring diabetics in terms of reducing clinical and angiographic restenosis was similar to that in patients with non-insulin-requiring diabetes. In insulin-requiring diabetics, angiographic restenosis in the analysis segment was reduced by >80% with the paclitaxel-eluting stent compared to the bare-metal stent, and the occurrence of diffuse in-stent restenosis was reduced by more than 90%. Indeed, among patients treated with the paclitaxel-eluting stent, both the late loss and loss index were numerically lower in insulin-requiring diabetics compared to those managed with oral agents alone, both within the stent and over the entire analysis segment. No safety concerns were noted in the overall diabetic cohort or insulin-requiring subgroup at one-year follow-up.

Previous studies examining the impact of drug-eluting stents in diabetics have reported conflicting results. In the 73 diabetic patients with focal lesions randomized to either the slow- or moderate rate-release, polymer-based, paclitaxel-eluting stent versus a bare-metal stent in the TAXUS II trial, angiographic binary restenosis rates were reduced from 20.5% with control stents to 0% with paclitaxel-eluting stents (20). In contrast, the non-polymer-based local delivery of paclitaxel did not significantly reduce restenosis in patients with or without diabetes in a large randomized trial utilizing a different stent platform (21). Nevertheless, it appears that utilization of an appropriate controlled-release mechanism such as a polymer may be required to deliver consistent paclitaxel dosing with reliable pharmacokinetic drug delivery.

The reasons for the excellent outcomes with the paclitaxel-eluting stent in diabetic patients are likely multifactorial. The primary mechanism of action of paclitaxel is the prevention of microtubule depolymerization, which is required for mitosis to progress through anaphase (22). Because paclitaxel modulates cell mitogenesis downstream from Ras/Raf/MAP kinase, and independently from PI3 kinase/PKb/mTOR signal-transduction pathways, it may be particularly effective in the diabetic with insulin resistance, inhibiting both insulin-dependent and -independent pathways that mediate neointimal hyperplasia (23–25). Moreover, in addition to being centrally involved in cell division, microtubules control multiple other cellular functions integral to restenosis, including cell signaling, activation, secretory processes, and migration (26–28). Because of these multifunctional actions, paclitaxel may attenuate pathways specifically up-regulated in the diabetic restenotic cascade. Finally, diabetics are known to have diffusely diseased arteries; it is possible that relative lack of vessel trauma at the edges with the TAXUS stent delivery system as deployed in the TAXUS-IV trial and/or paclitaxel-mediated cell-to-cell signaling processes contribute to the preserved efficacy seen with this drug-eluting stent at the stent margins in patients with diabetes (27,29).

The principal limitation of this study is that, although randomization was stratified by diabetic status, the trial was not powered to show significant reductions in clinical and angiographic end points in patients with diabetes; thus, the results of this subset analysis, though pre-specified, must be considered hypothesis-generating and not definitive. Moreover, the number of patients in the insulin-requiring group was relatively small (the likely reason why the reduction in TLR was only of borderline statistical significance with the paclitaxel-eluting stent in this cohort), especially those with angiographic follow-up; greater experience with both drug-eluting stents is required to fully characterize the safety and efficacy of these devices in insulin-requiring diabetics. Larger studies are also required to more accurately define event rates, which were uncommon in this study, including stent thrombosis. Finally, the most complex diabetic patients were excluded from enrollment, including, for example, those with multivessel and diffuse disease. In this regard, a large-scale randomized trial funded by the National Heart, Lung, and Blood Institute will soon begin in which an unselected diabetic cohort with multivessel disease will be randomized to drug-eluting stent implantation (paclitaxel- or sirolimus-eluting) versus surgical revascularization.

Conclusions and clinical implications.   Despite the above caveats, the one-year clinical and nine-month angiographic results after implantation of the polymer-based paclitaxel-eluting stent as shown in the TAXUS-IV trial suggest that a new standard has emerged for the percutaneous treatment of diabetic patients. The TAXUS stent proved safe and markedly effective in reducing restenosis in the diabetic patient, whether treated with oral hypoglycemic agents or insulin, such that for the first time the restenosis rate of diabetic patients was reduced to that seen in the non-diabetic.


   Footnotes
 
The names of the investigators, research coordinators, and institutions participating in the TAXUS-IV trial appear in reference 11.

1 Drs. Hermiller, Ellis, and Stone have served as consultants for Boston Scientific Back

2 Dr. Russell is an employee of and equity holder in Boston Scientific. Back


   References
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