Pharmacology is a favorite subject of mine and so I think it super interesting to discuss. Unfortunately, this post may be one of my most boring write ups. Luckily, the content makes up for it! (Hopefully). I bolded the key points to help. This one is a quickie.
- Clopridogrel (Plavix)
Loading Dose: 300mg or 600mg depending on preference of cardiologist
Clopidogrel is a thienopyridine which irreversibly blocks the P2Y12 platelet receptor. The CURE trial (n = 12,562) helped show the efficacy and safety when combined with aspirin in patients with NSTE. The combination reduced the composite primary outcome of cardiovascular death, non-fatal MI, or stroke by 2% absolute risk (9.3% vs. 11.4%) vs aspirin alone. A 1% absolute increase in major bleeding events was noted, but there was no significant increase in life threatening or fatal bleeds. Typical loading dose is 300 mg however, for some patients with PCI it is common practice to use a higher loading dose of clopidogrel (600 mg) in order to more rapidly achieve full antiplatelet effect. Clopidogrel is a prodrug. Genetic polymorphisms of CYP3A4 and CYP2C19 cause variation in the effectiveness of clopidogrel. Due to the irreversible binding it has a slow in offset (over several days) which can be clinically important when urgent CABG is required.
2. Prasugrel (Effient)
Loading Dose: 75mg
Prasugrel also requires metabolism to an active form since it is a prodrug. Metabolism is rapid due to esterases, and a single CYP450 so there is minimal change in metabolism. In TRITON-TIMI there was a reduction in recurrent cardiovascular events in the prasugrel treated group vs clopidogrel (9.3% vs. 11.2%), driven by a reduction in non-fatal MI (7.1% vs. 9.2%). A significantly lower rate of stent thrombosis was also seen in the trial with prasugrel (1.1% vs. 2.4%). More bleeding, however, was observed in the prasugrel arm (2.4% vs. 1.8%) and with an increase in fatal bleeding (0.4% vs. 0.1%). Patients with a previous TIA or CVA experienced net harm with prasugrel thus the drug is contraindicated in these patients.
- Ticagrelor (Brillinta)
Loading Dose: 180mg
Ticagrelor the first non-thienopyridine ADP blocker and is a cyclopentylazopyrimidine. It reversibly binds to the P2Y12 platelet receptor. In addition to reversible inhibition of the P2Y12 receptor, ticagrelor also inhibits adenosine reuptake in cells. This can cause additional complaints of dyspnea (5% of patients) and bradycardia in addition to bleeding side effects. The PLATO study compared ticagrelor (180 mg loading dose, followed by 90 mg twice daily) with clopidogrel (300–600 mg loading dose, followed by 75 mg daily) in 18,624 patients who presented with either STEMI or NSTEMI. Ticagrelor was associated with a 2% absolute risk reduction in the primary endpoint of vascular death, MI, or stroke compared with clopidogrel. All-cause mortality (4.5% vs. 5.9%) and stent thrombosis (1.4% vs. 1.9%) were lower with ticagrelor. There was no difference in major bleeding or blood transfusions. The ATLANTIC trial (n = 1875) assessed whether pre-hospital ticagrelor loading was superior to delayed in-hospital ticagrelor. The co-primary outcomes were related to arterial patency at angiography with no different between the two groups. Misdiagnosis of STE was identified in 10% of patients. The difference in timing of loading dose was approximately 30 min. Furthermore, it was also noted that opiate administration impaired oral absorption of ticagrelor. Further, it was also noted that opiate administration impaired oral absorption of ticagrelor. This may be a potential limitation of ALL oral P2Y12 receptors in the STEMI setting.
- Cangrelor
Cangrelor is an IV form of the cyclopentylazopyrimidine ADP blocker. It has a faster onset and offset through reversible inhibition of the P2Y12 receptor. It has a very short half-life (<10 min), thus platelet function can be restored within a couple of hours of discontinuation of the infusion. Cangrelor has been studied in three large trials, 70% of whom had presented with an ACS. A meta-analysis of these trials demonstrated a reduction in periprocedural death, MI, ischemia-driven revascularization and stent thrombosis for cangrelor vs clopidogrel (3.8% vs. 4.7%).
Reference:
Brown. Continuing Cardiology Education, 2017; 3(1) pp11-21
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