Platelet aggregability and occurrence of restenosis following coronary angioplasty

International Journal of Cardiology 60 (1997) 227–231

Platelet aggregability and occurrence of restenosis following coronary angioplasty a, a b b b Pravin K. Goel *, Madhukar Shahi , A.K. Agarwal , S. Srivastava , P.K. Seth a

Department of Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226 014, India b Industrial Toxicology, Research Centre, Lucknow, India Received 15 August 1996; accepted 2 April 1997

Abstract Restenosis following percutaneous coronary angioplasty (PTCA) is a complex medical problem occurring in nearly a third of the patients undergoing PTCA with no single definite predictor demonstrated in an individual patient. Platelets are known to play an important role in the pathogenesis of the restenotic process. However, no known parameter of platelet function or activity has been studied as a risk factor predicting the occurrence of restenosis. We prospectively assessed platelet activation in twenty two consecutive patients with stable angina who underwent a successful PTCA for single vessel coronary artery disease. Platelet activation levels were measured using aggregability curves derived from unclotted blood samples on a platelet aggregometer using varying concentrations of adenosine di-phosphate (ADP) in the following time sequence: (1) Basal i.e. pre-PTCA, (2) post-PTCA day 1, (3) post-PTCA day 7, and (4) post-PTCA day 28. Occurrence of restenosis was studied using angiographic follow-up in all patients. At follow-up, seven of the twenty two patients studied developed restenosis. There was no significant difference or any specific trend noted over time in the levels of platelet aggregability in the study group as a whole (basal: 30.0615.4%, post-PTCA day 1: 32.5616.1%, post-PTCA day 7: 34.6615.4% and post-PTCA day 28: 32.6616.1%). However, when the patients were subgrouped into those with and without restenosis, the patients with restenosis had a significantly higher basal platelet aggregability (38.7616.3%) versus those who did not develop restenosis (25.0612.1%), p50.0128. We conclude that patients developing restenosis after PTCA have a significantly higher basal platelet aggregability and this could be used as a marker for its occurrence in an individual patient.  1997 Elsevier Science Ireland Ltd. Keywords: Platelet aggregability; Biological risk factors; Adenosine di-phosphate; Restenosis, predictors of

1. Introduction Since its introduction by Gruentzig in 1977 [1], percutaneous transluminal coronary angioplasty (PTCA) has become an established non-surgical technique for myocardial revascularization. Increased operator experience and advances in technology have resulted in primary success rates of .90–95% [2]. However, the occurrence of restenosis in 30–40% of patients remains a major limitation [3–6]. *Corresponding author.

Although many biologic [7,8], clinical i.e. patientspecific [6,9–12], morphologic i.e. lesion-specific [6,9,12–14], and procedural i.e. operator technique and device-related [4–6,9,12–14] factors have been related to the occurrence of restenosis, none have been shown to predict or preclude its occurrence in a given patient [15]. Platelet adhesion and activation at sites of angioplasty-mediated vascular injury [16,17] have long been shown to play a central role in the early reparative cellular response [18] leading to the formation of a neointima. An exaggeration of this neointimal prolif-

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eration has been implicated in restenosis development [8,19,20]. This may well be due to excessive vascular injury [21] or due to as yet undefined stimuli which may include inherent differences in platelet responsiveness to similar injury. However, no known parameter of platelet function has been studied so far as a marker to risk-stratify patients for development of restenosis. Therefore, we aimed to study, prospectively, platelet aggregability in patients undergoing a successful single vessel coronary angioplasty, to look for differences, if any, in the levels of platelet activation before and after the procedure and their correlation with the future occurrence of restenosis.

2. Methods

2.1. Patients We prospectively studied twenty two consecutive patients with chronic stable angina pectoris undergoing successful elective PTCA for single vessel coronary artery disease. A successful angioplasty was defined as a residual diameter stenosis of less than 20% on the immediate post-angioplasty angiogram so as to exclude the element of residual stenosis in the occurrence of restenosis [6,9,14], with no flow-limiting split, and without the occurrence of death, myocardial infarction or the need for emergency bypass surgery during hospitalization. Patients with a split of grade C or more were excluded from the study. All stenoses were measured with callipers since this is a readily-available technique and correlates closely with computer-quantitated methods [22].

2.2. PTCA protocol PTCA was performed by a standard femoral approach using a balloon: artery ratio of 0.9–1.0:1.0 [23]. All patients were pre-treated with aspirin 325 mg per day, dipyridamole 150 mg per day and nifedipine 30 mg per day. These medications were continued throughout the study period. Intravenous heparin 10 000 i.u. was administered before dilatation, with additional heparin given to maintain an activated clotting time (ACT) of $300 s during the procedure.

2.3. Platelet aggregation study Platelet aggregation was measured by the method of Salvemini et al. [24] using platelet rich plasma (PRP) from blood drawn in the following time sequence: (1) basal i.e. pre-PTCA, (2) post-PTCA day 1, (3) post-PTCA day 7, and (4) post-PTCA day 28.

2.3.1. Preparation of platelet rich plasma ( PRP) 5 ml blood was drawn with a sterile syringe containing 0.5 ml 3.8% sodium citrate as anticoagulant from every patient and centrifuged at 8003g for 10 min. The PRP was separated from the top of the centrifuge tube and used for the aggregation study. 2.3.2. Platelet aggregation Aggregation was studied in an aggregometer. 500 ml PRP was incubated at 378C in the aggregometer for 2 min followed by addition of 2 mm adenosine di-phosphate (ADP) with continuous stirring at 1000 rpm. Platelet aggregation was recorded up to 5 min and expressed in terms of percent light transmission after stimulation with the agonist ADP. Results were expressed in terms percent aggregation. 2.4. Follow-up All patients were followed up and assessed clinically at 15 days, 3 months and 6 months, and underwent treadmill exercise testing at 15 days and 6 months after PTCA. Coronary angiography was performed at 6 months, or earlier, if indicated by symptoms or treadmill testing. Restenosis was defined as a luminal diameter loss of more than 50% at follow-up coronary angiography [25].

2.5. Statistical analysis All data are expressed as mean6S.D. Categorical variables were compared using the chi-square test with Yates’ correction and continuous variables were compared using Student’s t test. A P value of 0.05 or less was considered statistically significant.

P.K. Goel et al. / International Journal of Cardiology 60 (1997) 227 – 231 Table 1 Demographic, clinical and angiographic characteristics Variable

Restenosis group

No restenosis group

P value

Age, years(SD) Men, n(%) Smokers, n(%) Hyper-tension, n(%) Cholesterol .240 mg dl -1 , n(%) Diabetes, n(%)

54(9) 7(100) 2(29) 2(29)

54(7) 13(87) 5(33) 4(27)

– 0.8281 0.7887 0.6740

0(0) 1(14)

1(6) 3(20)

0.6895 0.7874

Vessels dilated LAD, n(%) LCX, n(%) RCA, n(%)

4(57) 1(15) 2(28)

7(47) 4(27) 4(26)

1.0000 0.9209 0.6742

Lesion type a A, n(%) B1, n(%) B2, n(%) C, n(%)

5(72) 1(14) 1(14) 0(0)

11(73) 3(20) 1(7) 0(0)

0.6742 0.7874 0.8281 -

a

AHA classification.

3. Results

3.1. Angiographic restenosis study Of the 22 patients who underwent a successful PTCA, seven patients developed restenosis, as defined, representing an overall restenosis rate of 32%. Patients who developed restenosis did not differ significantly from those who did not develop restenosis in their demographic, clinical or angiographic characteristics (Table 1).

3.2. Platelet aggregation study Platelet aggregability in the basal state and at day 1, day 7 and day 28 post-PTCA is shown in Table 2. There was no significant difference or any specific trend seen in platelet aggregability in the time Table 2 Platelet aggregability Time

Restenosis group

No restenosis group

P value

Pre-PTCA Basal

38.7(16.3)

25.0(12.1)

0.0128

Post-PTCA Day 1 Day 7 Day 28

36.0(11.2) 34.3(20.5) 37.3(13.9)

33.9(12.8) 39.9(15.8) 34.0(18.2)

0.3697 0.2577 0.3811

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sequence studies. However, on subgrouping the patients into those who developed restenosis (n57) and those who did not develop restenosis (n515), the basal platelet aggregability pre-PTCA was significantly higher in the restenosis group when compared with the no-restenosis group viz. 38.7616.3% vs. 25.0612.1% (P50.0128). The mean total aggregability did not differ significantly in the two groups; restenosis group: 36.6615.0% vs. no restenosis group: 33.1615.2% (P value50.1828).

4. Discussion Since first reported [1], PTCA has gained widespread acceptance and use, though its Achilles’ heel remains the occurrence of restenosis [26]. Endothelial injury following angioplasty triggers off a ubiquitous, complex, and primitive vascular healing response with the formation of a neointima, resulting in loss of lumen caliber at the injured site and restenosis [16,17,20]. Although pathophysiologic mechanisms and the molecular basis for this restenosing process [16–20] have been elucidated in recent times, we are yet to unravel how this reparative response is orchestrated and controlled. Does restenosis represent one end of the spectrum of the normal Gaussian distribution of luminal diameter loss following PTCA [27] or is it a ‘‘yes’’ or ‘‘no’’ phenomenon occurring in some patients who due to some undetermined mechanism, show and excessive intimal reparative response is an unanswered question. Recently, proponents of restenosis ‘‘anti-theories’’ have implicated vascular recoil and remodelling as a cause of restenosis [28,29]. Although reports do suggest a reduction in restenosis frequency with endovascular stenting [30,31], which by providing a mechanical scaffolding is theorised to obviate recoils and remodelling, treatment failures persist and have been shown to be due to persistent in-stent neointimal hyperplasia. Experimental data support the central role of platelets [16–18] in the early cellular response leading to restenosis. Platelets adhere and aggregate at sites of endothelial denudation following coronary angioplasty and the resultant platelet activation plays a major role in initiating the cellular migration and proliferation essential for neo-intima formation

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[19,20]. A greater degree of angioplasty-induced vascular injury has been linked to a higher restenosis risk [21], presumably following greater platelet aggregation and activation prompting the emergence of potent platelet anti-aggregants like glycoprotein IIB / IIIa antagonists in the prevention of restenosis. Although various patient-related [6,12], lesion specific [6,9,12–14] and procedural [4,6,9,12–14] factors have been identified as markers of risk for restenosis, none has been shown to predict its occurrence in an individual patient [15]. In our study, there were no significant demographic, clinical or angiographic differences between the two groups to account for differences in platelet aggregability or restenosis risk. Our study shows that mean platelet aggregability using adenosine di-phosphate was significantly higher in the groups developing restenosis as compared to the group which did not develop restenosis. This suggests that one of the critical factors modulating the degree of intimal hyperplasia in an individual patient could be the basal level of platelet activation. The difference in the platelet aggregation between the restenosing and non restenosing group however did not maintain itself post angioplasty. This we feel could be related to some time sequence change in platelet aggregability post angioplasty which was not evident in our study because of the smaller numbers and may stand out if larger numbers are studied. Benchimol et al. [7] reported a heightened basal pro-thrombotic profile including higher fibrinogen and platelet factor 4 levels in patients developing restonosis after PTCA. Additionally, inherent difference in platelet reactivity in a third of the population could be responsible for the magic number of ‘‘30’’ in nearly all studies of restenosis following PTCA. The reasons for this heightened basal platelet reactivity may be related to unknown genetic, haemostatic or rheologic factors which need further study.

5. Conclusion We conclude that a high platelet aggregability in the basal state is an inherent characteristic that defines a group of patients prone to restenosis after PTCA, and that this may be a potential marker for its

occurrence in an individual patient. The factors responsible for this heightened platelet aggregability remain enigmatic and deserve further investigation.

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