Triple Versus Dual Antiplatelet Therapy after Coronary Stenting in Patients Undergoing Elective PCI with Drug Eluting Stents: Impact on Stent Thrombosis

Triple Versus Dual Antiplatelet Therapy after Coronary Stenting in Patients Undergoing Elective PCI with Drug Eluting Stents: Impact on Stent Thrombosis
Ahmed Mowafy MSC, MD, FSCAL
A. prof. of critical care medecine
fellow of the american society of cardiovascular and interventoin
member of the european sosiety of cardiology
Objectives: The study evaluated safety and efficacy of triple antiplatelet therapy with Aspirin, clopidogrel and cilostazole after coronary stenting using drug eluting stents.
Background: Triple antiplatelet therapy might have beneficial effect to prevent thrombotic complications in patients undergoing coronary stenting.
Methods: Patients undergoing successful coronary stenting using drug eluting stents were divided into dual antiplatelet therapy (Aspirin plus clopidogrel group I, n=36) and triple antiplatelet therapy (Aspirin plus clopidogrel plus cilotazol groupII, n=36). The primary end point included death, myocardial infarction, target lesion revascularization and stent thrombosis within six months. The secondary end point was the side effect of the study drug, including major bleeding, hepatic and hematological complications.
Results: The incidence of stent thrombosis was lower in the triple antiplatelet group Vs. the dual antiplatelet therapy group(0% in group II Vs. 8, 3% in group I).
The overall adverse drug effects, including major bleeding, neurtropenia and hepatic dysfunction were slightly different between the two groups with no need for discontinuation of the drug.
Conclusion: Compared with the dual antiplatelet regimen, triple antiplatelet therapy seemed to be more effective in preventing thrombotic complications after stenting without an increased risk of side effects. Triple antiplatelet therapy may be applied safely in patients on lesions with high risk of stent thrombosis.
Key Words: Stent thrombosis – Antiplatelet – Cilostazole – Clopidogrel – Drug eluting stents.
Introduction
Restenosis within a segment of a diseased coronary artery after percutaneous transluminal coronary angioplasty (PTCA) has been a limiting
factorin this type of intervention since its introduction nearly 30 years ago [1]. In contrast to restenosis after balloon angioplasty – which is the result of multiple factors, treatment strategies to prevent restenosis after coronary stenting focus on limiting cell proliferation [2]. A thrombotic response involving a triggering of platelet adhesion, activation and aggregation as well as thrombus formation occurs within days of the stenting. Stent thrombosis is now more evident in the era of DES. Although drug-eluting coronary stents (DES) are an important medical innovation reducing clinically relevant restenosis, late and very late stent thrombosis due to the DES-inherent delayed endothelialization, is a continuous concern.
Cilostazol is a potent oral antiplatelet agent with a rapid onset of action that selectively inhibits phosphodiesterase III, a mechanism different from adenosine diphosphate (ADP) receptor antagonists[3,4]. Previous studies have suggested that cilostazol has similar antiplatelet effects as ticlopidine [5] or clopidogrel [6]. Adding cilostazol to aspirin and clopidogrel regimen was shown to provide additional suppression of the expression of P-selectin,a marker of platelet activation, in 76.6% of study population, suggesting synergistic or additive antiplatelet effects [7]. From these theoretical, experimental and clinical backgrounds, we assumed that triple antiplatelet therapy with aspirin, ADP receptor antagonists and cilostazol might have a beneficial effect on the prevention of thrombotic complications following coronary stenting. In this study we evaluated the safety and efficacy of triple antiplatelet therapy of aspirin, clopidogrel and cilostazol compared with dual antiplatelet therapy with aspirin and clopidogrel in patients undergoing successful PCI with drug eluting stents.
Study patients:
From May 2006 to January 2008, 72 consecutive
patients (pts) who underwent successful coronary stenting were eligible for this study. Inclusion criteria included symptomatic coronary artery disease or documented myocardial ischemia by treadmill stress testing or thallium single-photon emission computerized tomography SPECT imaging,with angiographic evidence of ≥ 60% diameter stenosis in patients planned to have PCI using drug eluting stents.
The exclusion criteria were contraindications for antiplatelet agents, severe left ventricular disfunction(ejection fraction ≤ 40%), left main coronary artery stenosis, known bleeding disorder,thrombocytopenia (<150.0000mm2), severe hepatic or renal dysfunction (serum creatinin ≥ 2mg/dl),administration of oral anticoagulants, glycoprotein IIb IIIa receptor antagonists and other antiplatelet agents as well as patients with recent myocardial infarction undergoing primary PCI. Also excluded are patients who did PCI to vein grafts and pts with instent restenosis.
Methods
Eligible pts who underwent successful coronary stenting were divided into two groups, a dual group(Aspirin plus Clopidogrel, n=36) and a triple therapy group (Aspirin plus Clopidogrel plus Cilostazol,n=36). All pts had 300mg loading dose of clopidogrel and were maintained on 75mg OD. Aspirin was given 150mg once a day, while Cilostazol was given 100mg b.i.d.
Stent implantation and angiographic analysis:
Stents were deployed in standard technique without using any complex technique «crush, minicrush, stenting …. ect». Patients received 10.000 units heparin during the procedure.
Angiographic data were analyzed for the following:
• Percent diameter stenosis.
• Minimal lumen diameter.
• Reference diameter before and after stenting.
All were measured during diastole after intracoronary nitroglycerin administration.
Clinical follow-up:
All pts were seen as out patients after discharge for one, three & six months. Complete blood count and blood biochemistry, including liver and renal function, were performed before and three months after the procedures.
The primary end points were the incidence of stent thrombosis, or major adverse cardiac events «MACE» including death, myocardial infarction and target lesion revascularization within six months.
The secondary end points included major bleeding,thrombocytopenia, neurtropenia, skin rash and liver dysfunction.
Acute stent thrombosis was defined as thrombotic stent closure within 24 hours after stent deployment and subacute stent thrombosis was defined as thrombotic stent closure 24 hours after stent deployment. Myocardial infarction was diagnosed when creatine kinase-MB was elevated morethan
three fold.
Statistical analysis:
Statistical analysis was done by using SPSS version 16. Descriptive statistics were used to describe patient characteristics (mean and SD for continuous data). Statistical significance was analyzed with student’s test for unpaired observations or by analysis of variance. A value of p<0.05 was considered to indicate statistical significance.
Results
Baseline characteristics:
There were no significant differences between the 2 groups in the baseline clinical characteristics except

Variable Group I Group II p value
Age 56.18±4.2 55.89±5.4 0.2
Gender M/F 28 (77.8%) 20 (55.6%) 0.05
Risk Factors:
• DM 26 (77.8%) 24 (66.7%) 0.6
• HTN 22 (61.1%) 16 (44.4%) 0.2
• Hypercholesterolemia 26 (72.2%) 14 (38.9%) 0.005
• Smoking 22 (61.1%) 24 (66.7%) 0.6
LV EF 59.1±3.2 59.6±2.7 0.3

in higher prevalence of hyperlipidemia in group I versus group II (Table 1).
Angiographic and procedural characteristics:
Patients in group I had more unfavorable anatomy than those in group II; however it did not reach a statistically significant va lue. Long lesion length was frequently encountered with group I than group IITable 2.

Variable Group I Group II p value
Treated artery:
• LAD 17 (47.2%) 15 (41.7%) 0.6
• LCX 13 (36.1%) 10 (27.8%) 0.5
• RCA 6 (16.7%) 11 (30.5%) 0.2
AHA/ACC lesion type:
• A 5 (13.9%) 4 (11.1%) 0.7
• B1 9 (25%) 12 (33.3%) 0.6
• B2 16 (44.4%) 18 (50%) 0.6
• C 6 (16.7%) 2 (5.6%) 0.1
Lesion length (mm) 32.6±38.7 22.39±3.4 0.01
Vessel diameter (mm) 3.08±0.24 3.04±0.17 0.02
Minimal luminal diameter:
• Baseline (mm) 0.85±0.07 0.90±0.06 0.06
• Final (mm) 3.08±0.24 3.04±0.17 0.02
Primary end point at six month:
A complete six month follow-up was available for all eligible pts. Stent thrombosis occurred in three pts in group I (8.3%) versus 0% in group II. The high
discrepancy in both groups may be attributed to low sample size (Table 3).
Acute stent thrombosis did not occur in both groups, whereas subacute stent thrombosis occurred in 3 patients (8.3%) in group I with mean time of occurrence of 3.8±2.9 days after the procedure.
No patients died during the six month follow-up period, where as 6 patients needed revascularization one more time, 4 pts (11.1%) in group I and 2 pts (5.6%) in group II (p=0.4).
Secondary end point at six month:
After six months follow-up: No major bleeding occurred, however, mild to moderate rise in liver enzymes occurred more in group II (6 pts 5. 6%)compared to 0% in group I, however it did not need discontinuation of the medication. Mild neurtropenia occurred in 2 pts in group II (5. 6%) Vs. no pts in group I. There were no skin rash or gastric problems in both groups
Discussion: This study demonstrates that triple antiplatelet therapy seems to be more effective in preventing stent thrombosis after coronary stenting, without an increased risk of side effects compared with the dual antiplatelet regimen.
The incidence of stent thrombosis was lower in the triple therapy group (0% in group II and 8. 3% in group I, p=0.008). Triple antiplatelet therapy significantly reduced the incidence of stent thrombosis when compared with dual therapy. However the low sample size may be responsible for these figures. A previous study with large number of patients comparing dual Vs triple antiplatelet therapy in pts undergoing PCI with bare metal stent, showed lower incidence of stent thrombosis in triple therapy group [8].
The exact mechanism of beneficial effects of triple antiplatelet therapy remains uncertain. Previous studies reported that elevated cyclic adenosinemonophosphate, either by ADP-receptor antagonist or inhibiting phosphodiesterase III by cilostazol,inhibits platelet aggregation and P-selectin release induced by thrombin, ADP and thromboxane A2 [9,10].
A marker of platelet activation, P-selectin is expressed exclusively by platelet activation, promotes
fibrin deposition and leads to the accumulation of leucocytes in areas of vascular injury and arterial thrombogenesis [11]. A recent report demonstrated that adding cilostazol to aspirin and clopidogrel regimen reduced platelet activation below the level achieved by aspirin and clopidogrel via additional suppression of P-selectin expression [7]. The incidence of poor suppression of P-selectin expression by clopidogrel ranged from 29% to 100% [12,13]. These previous reports support the enhanced antiplatelet effects of triple regimen. Furthermore, like ADP-receptor antagonists, Cilostazo significantly inhibited platelet aggregation induced by ADP and other agonists, which suggests the possibility of a synergistic or additive effect for inhibition of platelet aggregation in response to ADP and other agonists [14].
The clinical benefits of triple therapy might be offset by an associated increase in major bleeding. The rate of major bleeding, however, was similar between the two groups. This result might be partially explained by a previous study showing that, compared with clopidogrel, cilostazol had similarly effective antiplatelet action without a significant increase in bleeding time [14]. The overall incidence of adverse drug reactions was also similar between the two groups. Therefore,cilostazol might be safely added to the convention adual antiplatelet regimen after coronary stenting in patients with high risk for stent thrombosis.
A few limitations needed to be addressed. First,the apparently low sample size of the study. Second,definitive statements may not be made regarding efficacy or applications of the results, directly to the patients, because of the non randomized nature of the study.
Finally, a large prospective randomized trial should be done to confirm the effects of triple antiplatelet regimen in patients or lesions with high risk of stent thrombosis.