¹3rd Year PGT, ²Professor, Department of General Medicine, ³MBBS. M.G.M. Medical College and L.S.K. Hospital, Kishanganj, Bihar, INDIA.

Email: dr.nishantmed@gmail.com

Table 1: Age distribution among three groups

Table 2: Sex distribution among three groups

Table 3: Demographic profile distribution among three groups

Table:4. Clinical profile distribution among three groups.

Table 5: Event within 30 days among three groups

Table 6: Event within 6 months among three groups

DISCUSSION

It is clear today that acute coronary syndromes result from a complex pathophysiological process of disruption of atheromatous plaque with superimposed platelet adhesion, activation, and aggregation, followed by activation of coagulation cascade and subsequent thrombus formation, Since platelets have a major role in this disease spectrum, antiplatelet therapy plays a central role in treatment and secondary prevention of acute coronary syndromes. As antiplalelet drug, aspirin has been the only available option for last several decades. Recently several new antiplatelet agents has been marketed among which clopidogrel seems to be most promising. In CAPRIE trial, clopidogrel was compared with aspirin regarding its role in prevention of thrombotic events in patients at high risk of ischaemic events. CURE investigators compared efficacy of combination of clopidogrel and aspirin with aspirin alone in patients with acute coronary syndromes without ST- elevation. But till date no study has been done to compare efficacy of clopidogrel, aspirin and their combination in the background of acute coronary syndromes. Hence our prospective study has been designed to evaluate the efficacy of clopidogrel, alone or in combination with aspirin in secondary prevention of acute coronary syndromes. In our study, reduction of end points of MI, recurrent ischaemia, cardiac death and revascularisation was marginally better with clopidogrel (31.3%) than aspirin (42.5%) which was not significant p>0.05. This discrepancy between two studies may be due to differences in population under study, end points, duration of study, and number of patients. CURE study¹², which is another important randomised, placebo controlled double blind trial, has been designed to show the benefit of adding clopidogrel to the regimen of treatment for patients with acute coronary syndromes without ST segment elevation who are receiving aspirin and other medications. Dose of clopidogrel was 300 mg single loading dose followed by 75mg/day, similar to our study. Aspirin was given at the dose of 75-325 mg daily. Follow up period was 3 to 12 months with mean duration of 9 months. The first primary outcome,- death from cardiovascular causes, non fatal myocardial infarction or stroke – occurred in 4.3% patients in combination (aspirin plus clopidogrel) group as compared with 15.0% patients in aspirin group. (P<0.001). The rate of second primary outcome- first primary outcome plus refractory ischaemia, was also significantly less in combination group (6.4% in combination group versus 20.0% in aspirin group). This result was expected because theoretically aspirin and clopidogrel inhibit two different steps in platelet aggregation (viz. Production and release of Thromboxane A₂, and blockade of ADP receptors respectively) and their efficacy are additive. The incidences of cardiac event were first evaluated at day 30. It was observed that death occurred in 2, 1 and 0 patients in groups A, B, and C respectively. Incidence of MI were 4, 3, 1; i.e. 10.0%, 6.3%, 2.1% respectively. Recurrent unstable angina developed in 4, 4, and 1 patient respectively, i.e. 10.0%, 6.3%. 2.1 % of patients. Altogether composite end points occurred in 10 patients in group A (25.0%), 8 patients in group B (16.7%) and 2 patients in group C (4.3%) at the end of 30 days. Analysis showed composite end points were significantly less in group 3 in comparison to group A and group B (Z= 2.48 and 1.63 respectively, P<0.05). On the other hand, difference of reduction of composite end points were not significant between group A and B. (Z=0.70 p value-0.24 ) There was two incidence of major adverse effect (viz. Intracranial haemorrhage) within 30 days which occurred in group B. Minor adverse effects occurred in 4 patients of group A (10.0%), 3 patients of group B (6.2%), and 5 patients in group C (10.6%). The difference was not statistically significant. [(P>0.1) Patients were followed up for 6 months. At the end of 6 months events were analysed by combining events within 30 days and events those occurred between day 31 and the end of 6 months. Total incidence of death were 3, 2 and 0 in groups A,B, and C respectively. Incidences of MI were 6, 5 and 2 in respective groups, i.e. 15.0%, 10.4%, and 4.3% patients. During this period UA occurred in 8, 8 and 3 patients respectively, i.e. 20.0%, 16.7%, and 6.4% of patients.  Overall incidence of composite end points were 17, 15, and 5 patients i.e. 42.5%, 31.3% and 10.6% in groups A,B, and C respectively. Analysis showed that benefit of combination therapy (Group C) was still persisting at the end of 6 months (For Group A and Group C, Z = 3.17 i.e. P<0.001, for Group B and Group C, (Z = 2.22 i.e. p Value - 0.01). On the other hand, ability of clopidogrel in reducing composite end points in comparison to aspirin was marginally superior but did not assume statistical significance. (Z = 0.86, p Value- 0.19) There was no further major adverse effect between 31st day and end of 6 months i.e. overall major adverse effect occurred in 2 patient in Group B as mentioned earlier. Total incidence of minor adverse effects were 7, 6 and 7 i.e. 17.5%, 12.5% and 14.9% respectively. There is no statistically significant difference (P>0.1). There was no evidence of haematological, renal or hepatic dysfunction in any of the groups. Our study is not only consistent with result of CURE, i.e. Combination is better than aspirin, but it also shows that combination is better than clopidogrel alone. Regarding adverse effects observed in CAPRIE, incidence of rash and diarrhoea were significantly more in clopidogrel group, whereas incidence of nausea, vomiting, indigestion; gastrointestinal haemorrhage, and abnormal liver functions were more in aspirin group. Incidences of bleeding, thrombocytopenia and neutropenia were not significantly different between two groups. In CURE trial, combination of clopidogrel with aspirin resulted in significantly increased incidence of major and minor bleeding. In our study, major adverse effect, which required discontinuation of therapy, occurred in only one patient in clopidogrel group (viz. intracerebral haemorrhage). Hence, its significance could not be compared with other groups. Incidences of minor adverse effects were not significantly different among three groups. Less incidence of bleeding in our study may be due to smaller sample size. There was no incidence of thrombocytopenia or neutropenia in our study.

CONCLUSION

Combination of aspirin and clopidogrel is significantly more effective than either drug alone in secondary prevention of acute coronary syndromes. This benefit is evident at 30 days and it becomes more significant at 6 months. Ability of clopidogrel in reducing composite end points is marginally superior in comparison to aspirin but the difference is not statistically significant.Incidences of adverse effects are not significantly different among three groups.

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