Comparison of clopidogrel versus ticlopidine for prevention of minor myocardial injury after elective coronary stenting

International Journal of Cardiology 87 (2003) 143–149 www.elsevier.com / locate / ijcard

Comparison of clopidogrel versus ticlopidine for prevention of minor myocardial injury after elective coronary stenting ¨ Yusuf Atmaca*, Rabih Dandachi, Sadi Gulec, Irem Dincer, Dervis Oral Ankara University Faculty of Medicine, Department of Cardiology, Ankara, Turkey Received 5 August 2001; received in revised form 11 March 2002; accepted 25 March 2002

Abstract We searched a randomized, double-blinded, prospective study that compared the effectiveness of clopidogrel versus ticlopidine for prevention of minor myocardial injury (MMI) and major clinical events (MCEs) after elective coronary stenting. A total of 158 consecutive patients (98 male, 60 female patients with a mean age of 59.365.4 years) were divided into two arms based on treatment with thienopyridines: group I, clopidogrel 13300 mg as a loading dose, and 1375 mg per day thereafter, group II, ticlopidine 23250 mg daily. Both thienopyridines were started on the same day as stent placement. Cardiac troponin T (cTnT) was measured immediately before and 12 h after the procedures. All patients were followed-up during the hospital stay (662 days) with respect to MMI and MCEs. The increase frequency and the amount of cTnT level in group I was found significantly lower compared with group II (5 vs.15; P,0.01; 0.3860.11 vs. 0.4460.12 ng / ml; P,0.001, respectively). Patients with elevated cTnT levels more likely to have C type lesion (P,0.004). Though there was a trend toward increased major clinical events rate in group II than those of group I, the statistical difference was not different (4 vs. 1.3%; P.0.05). The present study showed that the combination of clopidogrel and aspirin was more effective than the combination of ticlopidine and aspirin in decreasing the rate of MMI.  2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Minor myocardial injury; Clopidogrel; Ticlopidine; Elective stenting

1. Introduction The use of intracoronary stents has increased greatly over the last decade and now intracoronary stents are widely used to treat vessel closure after balloon angioplasty or electively during angioplasty to decrease the rate of restenosis [1]. Patients undergoing coronary stent implantation may be at increased risk of elevated cardiac enzymes than those treated with balloon angioplasty alone due to increased platelet activation caused by the intracoron*Corresponding author. Kent Koop, Mahallesi, 11 Cadde, Final Sitesi, 2-B Blok, No. 8 Batikent, Ankara, Turkey. Tel.: 190-312-256-9710; fax: 190-312-312-5251. E-mail address: [email protected] (Y. Atmaca).

ary metallic stents [2,3]. Although the clinical significance of the elevated cardiac enzymes is controversial, recent studies have suggested that even seemingly minor elevations in cardiac enzymes after coronary interventions are associated with poor prognosis [4,5]. Therefore, the avoidance of minor myocardial injury (MMI) after coronary interventions undoubtedly remains a desirable goal [6]. The comparative studies regarding the effectiveness on stent thrombosis rate of two regimens with ticlopidine plus aspirin and clopidogrel plus aspirin indicated different results. In some study, ticlopidine and aspirin was found to be having a higher stent thrombosis rate than clopidogrel and aspirin [7–9], whereas other studies reported similar stent throm-

0167-5273 / 02 / $ – see front matter  2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 02 )00316-9

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bosis rate between two regimens [10,11]. On the other hand, there is no available data that compares ticlopidine plus aspirin with clopidogrel plus aspirin with respect to MMI that is associated with poor prognosis. Therefore, we searched a randomised, double-blinded, prospective study that compared the impact of clopidogrel versus ticlopidine on MMI and major clinical events (MCEs) in hospitalization period in patients undergoing elective coronary stenting.

2. Materials and methods

2.1. Patient selection From March 1998 to January 2001, a total of 168 consecutive patients undergoing elective single vessel PTCA with stenting were enrolled prospectively in the study. The inclusion criteria of the study were the patients with Canadian Cardiac Society Class-II stable angina pectoris and de novo lesions in large native coronary arteries. Patients with unstable angina, acute myocardial infarction within 2 weeks, 12-lead resting electrocardiogram with right or left bundle branch block, paced rhythm or complete atrioventricular block, aorta-coronary by-pass operation within 2 weeks, renal dysfunction, pericardial disease, cardiomyopathy, and recent myocarditis were accepted as an exclusion criterion. Furthermore, patients who received a stent as a bailout indication, and patients who were given tirofiban during the procedure were also excluded. Randomization was performed using a closed envelope system without patient stratification. In this double-blinded, prospective randomised study, patients were divided into two arms based on treatment with thienopyridines: group I, clopidogrel 13300 mg as loading dose, and 1375 mg per day thereafter, group II, ticlopidine 23250 mg daily. Both thienopyridines were started on the same day as stent placement. All patients received aspirin 13300 mg per day concomitantly. Furthermore, all patients were on the standard treatment of stable angina. Both ticlopidine and clopidogrel were discontinued after 1 month in all patients. The primary end-point of the study was the procedure-related MMI assessed by cardiac troponin

T (cTnT) at 12 h after the procedure and the secondary end-point of the study was the major clinical events (death, acute myocardial infarction, and repeat revascularization via either by-pass surgery or percutaneous coronary intervention). The study protocol was approved by the local ethics committee and a written informed consent was requested of all patients.

2.2. Invasive procedure Coronary angiography was made by Judkins technique from right femoral artery. Coronary lesions were assessed by multiple orthogonal views with coronary angiography and visually evaluated for morphologic features similar to those reported by the ACC /AHA [12]. Balloon angioplasty and stent implantation was performed by three different invasive cardiologists according to standard clinical practice. Coronary dissection, sub-optimal result was accepted to be stent indications after pre-dilatation. Coronary dissection was defined as the presence of a curvilinear filling defect parallel to the vessel lumen, contrast material outside of the vessel lumen persisting after passage of the contrast, or a spiral defect obstructing the vessel lumen. Sub-optimal result was defined as .50% residual diameter stenosis after pre-dilatation. A standard regime of drug treatment was instituted at least 48 h before the procedure. Intravenous heparin (10,000 U) was administered at the beginning of the procedure followed by additional boluses as needed to maintain activated clotting time .300 s. Intracoronary nitroglycerin 0.1–0.3 mg was given liberally during the procedure. Heparin infusion was discontinued at the termination of invasive procedure in all patients. A 6F guiding catheter was used in all patients and changed for an 8F guiding catheter in patients of whom coronary intervention was decided during the coronary angiography. The number of balloon inflation, balloon inflation pressure and the total balloon inflation time (BIT) were recorded during the interventions. Results before and after coronary interventions were evaluated quantitatively by coronary angiography (Philips DC). Angiographic success was defined as ,20% residual diameter stenosis after stent implantation and no major complications. Major

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complications included death, acute myocardial infarction, emergency by-pass surgery or percutaneous coronary intervention.

2.3. Electrocardiographic monitoring and ECG All patients were monitored continuously during the interventions and then transferred in an intensive care unit after the procedure. A 12-lead ECG was taken just before and immediately after coronary stenting for exclusion of an acute ischemia. A significant ST-segment depression was defined as horizontal or down sloping depression of ST segment .0.1 mV and 0.08 s after the J point that persisted more than 1 min.

2.4. Blood sampling Heparinized venous whole blood was used for the measurement of cTnT. Blood samples were drawn from an antecubital vein just before and 12 h after the procedure and then put in a heparinized collection vial. Special cardiac pipettes were used for transferring blood from the collection vial to the test strip. The needle of the cardiac pipette was inserted through the rubber closure of the vial and then 150 ml anticoagulated blood was drawn up from the stoppered vial. The blood sample within the cardiac pipette was applied to the test strip and then serum cTnT concentration was measured by ‘‘Cardiac T Quantitative’’ equipment (Boehringer Mannheim, Germany). The results were soon evaluated within 20 min by ‘‘Cardiac Reader’’. The method is based on a single-step sandwich principle and two monoclonal antihuman cardiac TnT antibodies. The principle of the assay has been reported elsewhere [13]. The lowest detection limit for the quantitative analyze was 0.05 ng / ml according to recommendation of the company. While the values remaining upper than 0.05 ng / ml were shown as quantitatively by Cardiac Reader, the lower values were assessed by qualitatively as negative.

2.5. Clinical follow-up All patients were followed during the hospital stay with respect to procedure related MMI and major clinical events (death, acute myocardial infarction,

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and percutaneous coronary intervention or bypass surgery). Moreover, patients were also observed with respect to major or minor bleeding complications during the hospitalization period. Deaths were classified as being cardiac origin if associated with congestive heart failure, acute myocardial infarction, or sudden cardiac death (,1 h after symptom onset). Revascularization of the target lesion was defined as either by-pass surgery or balloon angioplasty involving the intervention segments. A diagnosis of acute myocardial infarction arising in connection with interventions was based on ECG changes, that is, a new Q wave or the evaluation of a current injury (ST segment elevation) lasting more than 1 day and the development of a T wave change; new specific ST segment elevation or depression $0.1 mV; and increase in serum CK, CK-MB activity.

2.6. Statistical analysis Continuous variables were expressed as mean6S.D. and were compared by Student’s t-test. Categoric variables were compared by the chisquared test. Comparison was made between clopidogrel group and ticlopidine group. Chi-squared test and Student’s t-test were used for the comparison of primary and secondary outcomes. A P value ,0.05 was considered statistically significant.

3. Results A total of 168 patients were underwent interventional procedure. Ten out of 168 patients enrolled in this study were excluded from the study for receiving a stent as a bailout indication and tirofiban treatment during the procedure, leaving 158 patients (98 male, 60 female patients with a mean age of 59.365.4 years) as the study population. Then, these patients were divided into two groups based on treatment with thienopyridines as mentioned in the study protocol: group I (n583), and group II (n575). There were no significant differences between groups I and II with respect to baseline clinical characteristics (Tables 1 and 2). However, the patients in group I had a higher frequency lesion in the right coronary artery, and the patients in group II had a higher ejection fraction. After coronary intervention were performed, 22

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146 Table 1 Demographic features of both groups

Age (year) Male / female (n) Family history for the CAD Hyperlipidemia Hypertension Diabetes mellitus Smoking

Group I (n583)

Group II (n575)

P

63.168.2 50 / 33 25 (30.1%) 24 (28.9%) 37 (44.5%) 18 (21.6%) 38 (45.7%)

62.167.4 48 / 27 20 (26.6%) 19 (25.3%) 31 (41.3%) 14 (15%) 33 (43%)

NS NS NS NS NS NS NS

CAD, Coronary artery disease.

patients had chest pain, but their 12-lead ECG and cTnT levels did not change. Fig. 1. Comparison of abnormal cTnT values at 12 h after stent implantation in both groups. cTnT, Cardiac troponin T.

3.1. Troponin T measurement Basal cTnT measurements were negative in all patients. Elevation of cTnT was observed in 5 (6.02%) patients in group I, and 15 (20%) patients in group II (Fig. 1). The mean cTnT value in patients with abnormal markers was 0.3860.11 ng / ml in group I, and 0.4460.12 ng / ml in group II. The amount and the frequency of abnormal cTnT levels in group I was significantly lower than those of group II (0.3860.11 vs. 0.4460.12 ng / ml, P,0.001; 6.02 vs. 20%, P,0.01). No significant difference was found between the patients with and without abnormal cTnT levels with respect to angiographic and demographic data in both groups. However, patients with elevated cTnT levels more likely to have C type lesion [eight

(40%) patients with abnormal cTnT vs. 17 (12.3%) patients with normal cTnT levels; P,0.004].

3.2. Angiographic data The diameter of the reference vessels was $2.5 mm in all patients who received stents. Initial stent deployment pressure was 12 atm in all patients and increased to 14 or 16 atm when required to achieve complete balloon expansion. The average number of inflation was between 2 and 4 in all patients. The total BIT and percent diameter stenosis were not different between two groups (118.363.2 s and 83.369.1% in group I vs. 119.463.3 s and

Table 2 Angiographic features of the both groups

Ejection fraction (%) Vessel distribution LAD RCA Cx No. of diseased vessels 1-vessel disease 2-vessel disease 3-vessel disease Lesion type A B C Diameter stenosis before PCI (%)

Group I (n583)

Group II (n575)

P

60.164.3

61.563.2

,0.02

28 (33.7%) 38 (45.7%) 17 (20.4%)

36 (48%) 23 (30.6%) 16 (21.33%)

NS ,0.04 NS

43 (51.8%) 30 (36.1%) 10 (12.0%)

33 (44%) 34 (45.3%) 8 (9.3%)

NS NS NS

38 (45.7%) 31 (37.3%) 14 (16.8%) 83.369.1

31 (41.3%) 33 (44%) 11 (14.6%) 85.166.8

NS NS NS NS

Angiographic features of the study population. LAD, Left anterior descending artery; Cx, circumflex artery; RCA, right coronary artery; PCI, percutaneous coronary intervention.

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85.166.8% in group II; P.0.05 for both). Of the 158 patients, 68 patients underwent stenting for nonocclusive coronary dissection, 46 suboptimal results after angioplasty, and 44 as a primer procedure. The rate of primary stenting was 20.4% in group I and 26.6% in group II (P5NS). A total of 195 lesions were opened and 188 stents were placed, 73 multiLink tristar or tetra, 56 hexacath, 34 jostent, 25 divisio stents. The number of stents was 98 (30 multiLink tristar or tetra, 22 hexacath, 28 jostent, 18 divisio stents) in group I and 90 (26 multiLink tristar or tetra, 20 hexacath, 30 jostent, 14 divisio stents) in group II. The statistical difference was not significant between two groups with respect to the number of stents and the type of stent (P5NS). Furthermore, there was no difference of abnormal cTnT frequency with respect to stent model, stent number and stent indications (P5NS). Side branch occlusion occurred in 19 (12.0%) patients after stenting, three (15%) of whom had an elevated cTnT (one in group I, two in group II). The diameter stenosis improved from 83.369.1% before dilatation to 11.364.2% after stenting in group I, and from 85.166.8% before dilatation to 9.465.1% after stenting in group II.

3.3. Clinical follow-up All patients were followed up during the hospitalization period (662 days). After procedure performed, there were no major clinical events up to the third day in patients with normal and abnormal cTnT levels in both groups. However, one patient with normal cTnT levels in group I and, one patient with abnormal cTnT levels in group II had a complications of non Q-wave acute myocardial infarction by the end of the first week. Another two patients in group II with abnormal cTnT levels underwent repeat percutaneous transluminal coronary angioplasty because of refractory angina. Other two patients who have acute non Q-wave acute myocardial infarction were subjected to by-pass surgery after repeat coronary angoigraphy. Though there was a trend toward increased major clinical events rate in group II than group I, the statistical difference was not different (4 vs. 1.3%; P.0.05). No major and minor bleeding complications were observed during the hospitalization period in both groups.

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4. Discussion The clinical relevance of cTnT release after coronary stenting remains a matter of debate. It has been shown that the postprocedural cTnT release has a prognostic relevance [14]. Reported incidence of MMI after coronary interventions ranges between 13 to 44%, and procedures involving stenting generally showed higher rates than those without [15,16]. Mechanisms behind the MMI associated with percutaneous revascularization procedures are longer ischemia duration, side branch occlusion, long dissection, severe periprocedural hypotension and distal embolization [17]. Other risk factors for the MMI is target lesion characteristics such as lesion complexity and degree of initial residual stenosis. This is consistent with our findings that 40% of patients with elevated cTnT levels had C type lesions. Furthermore side branch occlusion occurred in 19 (12.0%) patients after coronary stenting, three (15%) of whom had an elevated cTnT. The strongest known predictors of MMI are coronary embolization, which is especially frequent after saphenous vein graft PTCA and directional atherectomy, and multivessel procedure [6]. But none of our patients with MMI had either of these procedures performed. Both human and animal studies have shown that the major source of the embolic debris is the plateletrich microaggregates [18,19]. Therefore, distal embolization can be partially prevented from the use of anti-platelet drugs such as thienopyridines and Gp IIb / IIIa inhibitors that have a synergistic effect [20– 24]. After coronary stent placement, platelet activation is a major determinant of subacute stent thrombosis [25]. Combination antiplatelet therapy with aspirin and thienopyridines become a standard practice over the last decade showed reduced complication rate in patients with stents [26,27]. Ticlopidine inhibits ADP-mediated activation of the glycoprotein IIb / IIIa receptors on platelet thus inhibits platelet activation and aggregation. However, long half life taking 5–7 days to reach near maximum effect, and causing an increased prevalence of certain rare but serious hematological side effect: i.e., trombositopenic purpura and severe neutropenia (0.8% of patients) are the major disadvantage of this drug [28–31]. Recently, a new thienopyridines in the same class as

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ticlopidine, clopidogrel, has been introduced which has the purported advantage of reduced incidence of severe neutropenia (0.04% of patients), once-a-day dosing, a lower cost, a better side effect profile, and a more rapid onset of action [32]. The half-life of clopidogrel is significantly shorter than that of ticlopidine, with ex vivo platelet aggregation studies having shown significant and dose-dependent inhibition of platelet aggregation as early as 2 h after a single dose [32]. In the present study, though there was a trend toward a lower major clinical events rate with clopidogrel plus aspirin than with ticlopidine plus aspirin, no statistical difference was found between these two regimens. On the other hand, we found that the combination of clopidogrel and aspirin was more effective than the combination of ticlopidine and aspirin in decreasing the rate of MMI. Since ticlopidine must be started at least 3 days before the procedure because of 5 to 7 day delay required for it to attain its full antiplatelet effect, it is reasonable that this high rate of MMI may be associated with its delayed action to achieve maximal protection at the time of coronary intervention. Given the favorable side effect profile, the lower cost, likely equivalence to ticlopidine with respect to major clinical events, and even more potent than ticlopidine for the prevention of MMI, clopidogrel and aspirin should become the first choice regimen for post-stent patients [33,34]. If ticlopidine is chosen as an antiplatelet regimen for the prevention of procedure related MMI, it should be started at least 3 days before the intervention in patients undergoing elective coronary stenting.

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