Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients With Diabetes Mellitus - DECLARE-DIABETES

Description:

Diabetic patients have a higher rate of restenosis following the implantation of coronary stents, compared with nondiabetics, even with drug-eluting stents (DES). The goal of this trial was to compare the effect of cilostazol, a phosphodiesterase inhibitor, with antiproliferative properties, in addition to aspirin and clopidogrel, on in-stent restenosis in diabetic patients undergoing implantation of DES.

Hypothesis:

Triple drug therapy with aspirin, clopidogrel, and cilostazol is superior to dual drug therapy with aspirin and clopidogrel in reducing in-stent late loss in diabetic patients undergoing DES implantation.

Study Design

Study Design:

Patients Screened: 423
Patients Enrolled: 400
Mean Follow Up: 6-9 months
Mean Patient Age: 60.9 years
Female: 42
Mean Ejection Fraction: 59%

Patient Populations:

• Age ≥18 years of age
• Angina pectoris or positive stress test
• Native coronary lesion, with diameter ≥50% and reference vessel diameter (≥2.5 mm)

Exclusions:

• Contraindication to cilostazol, aspirin, or clopidogrel
• Left main disease
• Graft vessel disease
• Ejection fraction <30%
• White blood cell count <3000/mm2
• Platelet count <100,000/mm2
• Alanine aminotransferase or aspartate aminotransferase ≥3 × upper limit of normal
• Serum creatinine ≥2.0 mg/dl
• Life expectancy <1 year secondary to noncardiac disease
• Planned bifurcation stenting
• Primary percutaneous coronary intervention for acute myocardial infarction within 24 hours
• Inability to follow protocol

Primary Endpoints:

In-stent late loss at 6 months

Secondary Endpoints:

• In-segment late loss
• Rate of restenosis >50% at 6 months
• MACE, stent thrombosis, target vessel revascularization at 9 months
• Major bleeding
• Minor bleeding
• Other adverse events
• Incidence of drug discontinuation

Drug/Procedures Used:

All patients received aspirin (200 mg daily) and clopidogrel (300 mg loading dose, 75 mg daily for at least 6 months) at least 1 day prior to the procedure. Patients in the triple group received 200 mg of cilostazol as a loading dose immediately after the procedure, followed by 100 mg twice daily for 6 months.

Concomitant Medications:

Glycoprotein IIb/IIIa inhibitors (4.5%), sirolimus-eluting stents (50%), and paclitaxel-eluting stents (50%)

Principal Findings:

A total of 400 patients were randomized (200 to the triple therapy group, and 200 to the dual therapy group). Patients were stratified based on the use of sirolimus- or paclitaxel-eluting stents. Baseline characteristics were similar between the two groups. The mean hemoglobin A1c was 7.7%, and about 16.3% of patients were insulin dependent. About 30% of patients in both arms had a total cholesterol >200 mg/dl.

At 6 months, the incidences of in-stent and in-segment late loss were significantly lower in the triple therapy group compared with the dual therapy group (0.25 ± 0.53 mm vs. 0.38 ± 0.54 mm, p = 0.025; 0.42 ± 0.50 mm vs. 0.53 ± 0.49 mm, p = 0.031). The incidence of in-segment restenosis was also lower in the triple drug therapy arm (8.0%) compared with the dual drug therapy arm (15.6%) (p = 0.03). In the subgroup analysis, patients receiving sirolimus-eluting stents had lower in-stent and in-segment late loss compared with patients who received paclitaxel-eluting stents (p < 0.001). Also, patients with sirolimus-eluting stents on triple therapy had the lowest incidence of in-stent restenosis, compared with dual therapy and sirolimus-eluting stents, triple therapy and paclitaxel-eluting stents, and dual therapy and paclitaxel-eluting stents.

At 9 months, the incidences of major adverse cardiac events (MACE), target lesion revascularization, stent thrombosis, myocardial infarction, and mortality were 3.0% vs. 7.0% (p = 0.07), 2.5% vs. 7.0% (p = 0.03), 0% vs. 0.5% (p = 1.0), 0.5% vs. 0.5% (p = 1.0), and 0.5% vs. 0% (p = 1.0) in the triple therapy arm compared with the dual therapy arm, respectively. Although the incidence of all bleeding was similar between the two groups (1.5% vs. 1.5%), the rate of drug discontinuation was significantly higher in the triple drug therapy arm (14.5%), compared with the dual drug therapy arm (2.5%) (p < 0.001). One major reason for this is a significantly higher incidence of rash in the triple drug therapy arm (7.5%) compared with the dual drug therapy arm (2.5%) (p = 0.04).

Interpretation:

Cilostazol has been shown to reduce the incidence of restenosis in patients undergoing percutaneous transluminal coronary angioplasty as well as bare-metal stents (CREST [Cilostazol for Restensosis]). The maximum benefit was noted in patients at highest risk for restenosis. The results of the current clinical trial indicate that triple antiplatelet therapy with cilostazol, clopidogrel, and aspirin is superior to dual antiplatelet therapy with aspirin and clopidogrel in reducing the incidence of late loss, angiographic restenosis, and the need for target lesion revascularization at 6 to 9 months in diabetic patients with DES implantation.

There are a few limitations of this study. The rate of drug discontinuation was high in the triple drug therapy arm (nearly 15%). Moreover, the incidence of DES in-segment restenosis in the dual drug therapy arm noted in this trial is much higher (15.6%), compared with other large DES trials in diabetic patients (~10%-11%).

Further studies on the long-term safety and efficacy of cilostazol along with aspirin and plavix in these patients are necessary.

References:

Lee SW, Park SW, Kim YH, et al. Drug-eluting stenting followed by cilostazol treatment reduces late restenosis in patients with diabetes mellitus: the DECLARE-DIABETES Trial (A Randomized Comparison of Triple Antiplatelet Therapy with Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation in Diabetic Patients). J Am Coll Cardiol 2008;51:1181-7.

Clinical Topics: Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Lipid Metabolism, Nonstatins

Keywords: Platelet Aggregation Inhibitors, Ticlopidine, Fibrinolytic Agents, Angioplasty, Balloon, Coronary, Vasodilator Agents, Purinergic P2Y Receptor Antagonists, Bronchodilator Agents, Paclitaxel, Cholesterol, Hemoglobins, Thrombosis, Neuroprotective Agents, Exanthema, Exercise Test, Phosphodiesterase 3 Inhibitors, Myocardial Infarction, Insulin, Drug-Eluting Stents, Sirolimus, Tetrazoles, Stents, Metals, Diabetes Mellitus


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