Acute coronary syndrome shares a common pathology of thrombus blocking the coronary arteries. Platelets play a major role in the formation and building the thrombus. Prasugrel (CS-747, LY640315) a novel thienopyridine recently approved. Parent drug is a prodrug, gets converted in to active metabolite and inhibits the GP IIb/IIIa receptor in platelets. TRITON TIMI-38 a land mark trial for prasugrel , based on the results FDA approved the molecule. Prasugrel is indicated in patients with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI) and also in Patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI.The most common adverse events is bleeding and thrombocytopenia.
Key words: Acute coronary syndrome, angina, thienopyridine
Introduction
Treatment with the thienopyridine (clopidogrel) reduces cardiovascular death and ischemic complications in patients with acute coronary syndromes (ACS), has been widely adopted in clinical practice. Platelets play a major role in the thrombus formation and ultimately block the blood vessel. Platelet activation and aggregation is the key factor in atherothrombotic vascular disease.1,2 Platelets are exposed to the sub-endothelial matrix at the sites of atherosclerotic plaque rupture, allowing adhesion to matrix proteins including collagen and von Willebrand factor.
Activation of the platelets by these interactions results in release of adenosine 5-diphosphate (ADP) which can induce secondary platelet activation and aggregation through ADP-induced platelet activation via the G-protein linked P2Y12 and P2Y1 receptors, further amplifying and propagating platelet activation induced by the primary activators.3,4,5 Activated platelets result in formation of platelet-rich thrombi, coronary vascular occlusion, cardiac tissue ischemia, and necrosis, what is collectively ACS. 6
Prasugrel (CS-747, LY640315), a third generation thienopyridine that achieves greater platelet inhibition than does clopidogrel with less variability7. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) trial demonstrated that, compared with clopidogrel, treatment with prasugrel resulted in a significantly lower rate of ischemic events and more bleeding among patients presenting with ACS with planned PCI.8
Mechanism of action:
Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.3 In addition, prasugrel was found to provide a greater platelet inhibitory effect in combination with aspirin not only for ADP-induced but also for collagen- and TRAP-induced platelet aggregation. 9
Fig1:
Pharmacokinetics:
Prasugrel is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites.10 Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The active metabolite's exposure (AUC) increases slightly more than proportionally over the dose range of 5 to 60 mg. Repeated daily doses of 10 mg do not lead to accumulation of the active metabolite. The absorption and metabolism are rapid; with peak plasma concentrations (Cmax) of the active metabolite occurring approximately 30 minutes after dosing.11 The active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to human plasma proteins. Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolites. The active metabolite has an elimination half-life of about 7 hours (range 2-15 hours).
Adverse effects:
The most common adverse effect seen in the clinical trial experience is bleeding and thrombotic thrombocytopenia12. The bleeding is from the GIT, epistaxis, hemoptysis, subcutaneous haematoma, post procedural haemorrhage, retroperitonel bleeding and retinal bleeding.
Interactions:
The risk of bleeding increases with the co-administration of heparin, warfarin and NSAIDS.
Indications:
Prasugrel is indicated to reduce the rate of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI) as follows:
Patients with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI).
Patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI.13
Prasugrel has been shown to reduce the rate of a combined endpoint of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke compared to clopidogrel. The difference between treatments was driven predominantly by MI, with no difference on strokes and little difference on CV death.14
Dosage and Administration: Initiate prasugrel treatment as a single 60 mg oral loading dose and then continue at 10 mg orally once daily. Patients taking prasugrel should also take aspirin (75 mg to 325 mg) daily. Prasugrel may be administered with or without food.
Dosing in Low Weight Patients: Compared to patients weighing ≥ 60 kg, patients weighing < 60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10 mg once daily maintenance dose. Consider lowering the maintenance dose to 5 mg in patients < 60 kg. The effectiveness and safety of the 5 mg dose have not been prospectively studied.
Clinical trials:
The land mark trial for the approval of prasugrel is TRITON-TIMI 38; based on the results, the FDA granted the approval of prasugrel.
In TRITON-TIMI 38 trial demonstrated that a prasugrel regimen of a loading dose of 60 mg and daily maintenance dose of 10 mg was significantly superior to the standard regimen of clopidogrel (300-mg loading dose and 75-mg daily maintenance dose) in preventing the composite end point of death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke during a median duration of therapy of 15 months.14 The reduction in the primary end point was driven by a significant 24% reduction in MI; significant reductions of 34% and 52% in urgent target vessel revascularization and stent thrombosis, respectively. 14 These benefits of prasugrel over clopidogrel in preventing ischemic events were achieved at the cost of an increased rate of Thrombolysis In Myocardial Infarction (TIMI) major non-coronary artery bypass grafting (CABG)-related bleeding. Net clinical benefit (death from any cause, nonfatal MI, nonfatal stroke, and nonfatal TIMI major non-CABG-related bleeding) significantly favored the use of prasugrel over the course of the trial.
Discussion:
Jernberg T 15 et al showed in his study that prasugrel achieves a greater Inhibition of Platelet Aggregation (IPA) compared to clopidogrel, the study also states that there are very few non- responders in the prasugrel arm. In the TRITON-TIMI 38, a subgroup analysis revealed that diabetic group in the prasugrel treatment arm has lesser ischemic events than non diabetic patients group.14
In a study by Varenhost C et al showed that the genetic variation of CYP2C19 alters the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel and hence good predictable response of this new molecule.16
During the FDA advisory committee, Dr. Braunwald chairman of TIMI group said that the thienopyridine drug, clopidogrel has higher variability among the individuals and delayed onset of action results in increased risks of MI and stent thrombosis, he also quoted that prasugrel had the potential to prevent 23,000 MIs ;8600 target vessel revasularisation;7,400 stent thrombosis and 4000 deaths -at a cost of 2,300 cases of nonfatal major bleeding (in non-CABG patients).17
As we need to see the both the sides of the coin, the adverse events are more with prasugrel than clopidogrel, in the TRITON-TIMI 38 the adverse events were of non fatal major bleeding.
Conclusion:
Its well known that the drug prasugrel has better efficacious than clopidogrel, but in order to stay in the market, a long time and a vast demographic exposure of the drug is required ,as the above results based on the clinical trial data with a controlled set of environment/patients. Though the bleeding is more with prasugrel, the right decision can be made with a wait and watch phenomenon…
