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NEWER ANTIPLATELET AGENTS IN CORONARY INTERVENTION
Ajit S Mullasari
Senior Consultant Cardiologist, Institute of cardiovascular Diseases, Madras Medical Mission, Madras
The preprocedural administration of aspirin reduces the risk of abrupt coronary closure after PTCA by 50-75% [1, 2] and is the standard therapy for all coronary interventions. Improved understanding of platelet aggregation however has revealed that aspirin has only a limited antiplatelet activity because it does not affect most agonist induced signal transduction cascades activating the Glycoprotein IIb/IIIa. [3] Only two of more than 90 known platelet agonists involved in aggregation seem to be inhibited by these agents. [4]GLYCOPROTEIN (GP) IIB/IIIB ANTAGONISTS
Glanzmann in 1918 described hereditary thrombasthenia which in later years was found to be due to dysfunction of Gp IIb/IIIa receptor, thus paving the way for drugs that targeted this receptor to inhibit platelet function.
Those under investigation fall into 3 major categories.
I. Abciximab (C 7E3, Reopro)
This Chimeric monoclonal antibody to Gp IIb/IIIa receptor had been tested extensively in high risk patients undergoing coronary angioplasty in atleast three randomized trials i.e. EPIC [5], EPILOG [6] and CAPTURE. [7]
a) Epic trial (evaluation of C7E3 fab in prevention of ischaemic complications)
2099 patients undergoing PTCA or atherectomy for unstable angina, acute myocardial infarction or high risk coronary morphology were randomized to a) Placebo, b) Bolus dose of Reopro, c) Bolus + Maintenance infusion of Reopro. All patients were also pretreated with Aspirin 325 mg OD and IV Heparin during and for about 12 hours after the procedure. The 30 day and 6 month outcome are described in Table 1.
Primary endpoint (30 days)% of Patients Reduction P Value Placebo 12.8 Bolus 11.5 10.4% 0.428 Bolus + Infusion 8.3 34.8% 0.008
Patients with Death, MI, or Revascularization% of Patients Reduction P Value Placebo 35.5 Bolus 32.6 7.1% 0.276 Bolus + Infusion 27.0 22.9% 0.001
As compared to placebo, patients receiving Reopro bolus + infusin had 35% and 23% reduction in ischaemic endpoints at 30 days and 6 months respectively. In addition Reopro reduced the need for target lesion revascularization at 6 months and reduced the incidence of non ‘q’ MI in atherectomy patients by 71%. In the EPIC trial, Reopro bolus + Infusion resulted in a ô 2 fold increase in major and minor bleeding events and transfusion compared to placebo. Major bleeding occurred most often at the femoral access site (72%) and was usually evident within 36 hours of treatment. Importantly, the incidence of intracranial haemorrhage, need for surgical intervention because of bleeding and CABG related major blood loss were similar between placebo and Reopro treated groups.
The cost effectiveness of the EPIC study showed that Reopro was associated with cost savings of $622 per patient due to fewer in hospital complications, which was offset by cost of $521 due to bleeding complications. Although Reopro costs $1407, 6 month costs were comparable due to 22% reduction in target lesion revascularisation and hospitalization in patients receiving Reopro.
b) Epilog Trial (Evaluation of PTCA to improve long term outome by C7E3 Gp IIb/IIIa receptor blockade)
1500 patients undergoing elective PTCA (Unstable angina and Acute MI were excluded) randomized to
1) Reopro + low dose weight adjusted Heparin,
2) Reopro + standard dose weight adjusted heparin,
3) Placebo + standard dose weight adjusted Heparin.
The results are summarised in Table 2.
Percentage of patients with death, MI or intervention% of patients Placebo + Std heparin 11.7% Abx + Low dose Heparin 5.2% ‘p’ value < 0.001 Abx + Std Heparin 5.4% % patients Placebo + Std heparin 3.1% Abx + Low dose Heparin 2.0% Abx + Std Heparin 3.5% ‘p’ value < 0.188
Hence patients randomized to Reopro (and low or standard dose heparin) had a lower incidence of death or MI compared to placebo (plus standard Heparin). This benefit was observed without an increase in major bleeding events. The trial was stopped prematively due to the beneficial effects of Reopro.
c) Prolog (Pilot Trial)
The aim of this study was to determine if weight adjusted heparin could improve the safety profile of Reopro while maintaining its clinical efficacy. Patients were randomized to receive in addition to Reopro, standard dose Heparin (100 units/kg, additional bolus to achieve ACT of 300 seconds) or low dose heparin (70 units/kg). Overall major bleeds unrelated to CABG was small (1.9%) and minor bleeding was lower in low dose heparin or early sheath removal group.
The other trials with Reopro are the CAPTURE (Reopro vs Conventional medical therapy 18-24 hrs prior to PTCA for unstable angina) which was stopped prematurely due to significant combined endpoint reduction in death, MI or reintervention in Reopro treated patients.
In conclusion, the major trials with Reopro show that bolus + infusion of Reopro reduces acute ischaemic complications and repeat target lesion revascularization in patients undergoing high risk PTCA or atherectomy (EPIC). Interim analyses also indicate that Reopro can reduce ischaemic complication in patients undergoing elective PTCA (EPILOG), as well as in hospital ischaemic complication in patients undergoing PTCA for medically refractory unstable angina (CAPTURE). Low dose weight adjusted heparin may be as effective with lower bleeding complications (EPILOG and PROLOG). There is a reduction in Target lesion revascularization and followup hospitalization (EPIC).II. INTEGRILIN
It is a short acting peptide Gp IIb/IIIa inhibitor. It is administered intravenously but unlike Reopro is short acting and highly specific for fibrinogen Gp IIb/IIIa receptor. It does not inhibit binding of fibronectin and von Willebrand factor binding to Gp IIb/IIIa. The IMPACT Trial (Integrilin to Manage Platelet Aggregation to Prevent Coronary Thombosis) used Integrilin to study its effects.
The results of this trial showed that there were fewer complications in patients receiving Integrilin as compared to placebo though there seemed to be a paradoxical reduction in adversee outcomes in elective but not high risk angioplasty subsets.III. LAMIFIBAN AND TIROFIBAN
These are short acting non peptide glycoproteins which have been studied in patients with unstable angina. In the PRISM - PLUS (Platelet Receptor Inhibition for Ischaemic Syndrome Management in Patients Limited to unstable angina), Tirofiban plus heparin therapy was associated with a significant reduction in ischaemic events at 7 days and to a lesser extent at 30 days including those subjected to catheterization and revascularization.CONCLUSION
The glycoprotein IIb/IIIa receptor inhibitors are an exciting new development in the treatment of coronary artery disease and have clearly been demonstrated to be beneficial in a broad spectrum of patients undergoing percutaneous coronary interventions.REFERENCES
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