Episode 31- Antiplatelet agents in ACS: Who rules the roost?


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Episode Summary:

In this episode, we discuss the pros and cons of the main antiplatelet agents used in the setting of ACS. Who comes out on top?

Show Notes:

Key Points:

Antiplatelet agents in ACS: Who rules the roost?:
– In the setting of ACS, dual antiplatelet therapy (“DAPT”) with aspirin plus a P2Y12 inhibitor is recommended to reduce the risk of arterial thrombosis
– Clopidogrel (Plavix) is the P2Y12 inhibitor recommended in patients with STEMI undergoing thrombolysis and in patients who are on anticoagulation who also require DAPT post-ACS (“triple therapy”). However, clopidogrel is a pro-drug that needs to be converted to its active form in the liver, making it ineffective in up to 30% of patients due to specific genetic polymorphisms and drug interactions
– Prasugrel (Effient) is also a pro-drug, but unlike clopidogrel it is not as affected by drug interactions or genetic polymorphisms. It shows a more rapid and complete antiplatelet effect as compared to clopidogrel. However, it is contraindicated in patients with a history of stroke or TIA, and it is not recommended in patients > 75 years of age or those weighing < 60 kg. It also has a narrow indication which mostly includes patients undergoing primary PCI in the setting of STEMI
– Ticagrelor (Brilinta) is not a pro-drug, and it shows higher and more consistent platelet inhibition than either of the other agents. It is also recommended in any ACS treatment strategy. However, this agent is dosed twice daily, can cause dyspnea (15% of patients), and is associated with ventricular pauses. We also have to keep our aspirin doses < 100 mg (usually 81 mg in the U.S.) post-ACS
ER-Rx Episode 31

References:

Norgard NB, DiNicolantonio JJ. Clopidogrel, prasugrel, or ticagrelor? A practical guide to use of antiplatelet agents in patients with acute coronary syndromes. Postgrad Med. 2013; 125(4): 91-102

Thachil J. Antiplatelet therapy- a summary for the general physicians. Clin Med. 2016; 16(2): 152-160

Transcript:

Hello and welcome to Episode 31 of ER-Rx. Today we’re going to compare the different antiplatelet agents within the setting of acute coronary syndrome (ACS). There are many nuances of these agents in this setting, including dose, timing, and duration. This is beyond the scope of this episode; all I want to do today is make you familiar with the three main agents used and discuss some pros and cons of each agent from the pharmacological perspective.

Platelet aggregation is the most important factor for the development of arterial ischemic events. So it makes sense that in certain scenarios such as coronary artery disease and ACS, antiplatelet therapy is key to improving patient outcomes. In the setting of ACS, all patients are given aspirin as well as a P2Y12 inhibitor as soon as possible-typically in the ER. This is referred to as “dual antiplatelet therapy” or DAPT. P2Y12 inhibitors block the binding of adenosine diphosphate to the P2Y12 platelet receptor, this inhibits platelet activation, degranulation, and aggregation. There are three main antiplatelet agents that are in use today.

Clopidogrel, or Plavix, is the one we are most familiar with. Clopidogrel is a thienopyridine pro-drug. Some pros of this agent is the fact that it is affordable, it is given once daily, and we have the most experience with its use. It is also the only agent with efficacy in patients undergoing thrombolysis in the setting of STEMI- which is important to note in settings that don’t have a cath lab. It is also the agent recommended in patients who are on anticoagulation who also require dual antiplatelet therapy post-ACS.

However, this agent comes with many cons. One of the biggest of which is that it is a pro-drug that has to be converted to its active form in the liver. This means that we can have variable responses between patients due to genetic variations. Data shows that up to 30% of patients on clopidogrel have an inadequate antiplatelet response, putting them at a greater risk of thrombosis. For example, one genetic polymorphism (ABCB1*2) is associated with the expression of more intestinal pumps that remove toxins and drugs like clopidogrel. And other polymorphisms (CYP2C19*2) is found in 25% of Caucasians, and this one encodes for a nonfunctional CYP enzyme that results in decreased conversion of clopidogrel to its active form. Both of these polymorphisms have been associated with a higher risk of death, MI, and stroke with the use of clopidogrel. This need for bioactivation by CYP enzymes also makes it more susceptible to drug-drug interactions with CYP-inhibiting or CYP-inducing medications. The poor performance of clopidogrel opened the door for newer, better agents.

One of these agents, prasugrel, or Effient, is also a thienopyridine pro-drug. However, its different from clopidogrel since the metabolism of prasugrel is very efficient and not altered much by variations in CYP activity. This means that genetics and drug-drug interactions are much less of a concern with this agent. Some pros of this agent are that it has consistently shown more rapid and complete platelet inhibition when compared to clopidogrel. And like clopidogrel, it is also a once-daily agent.

However, this agent comes with some very important cons. It is associated with higher bleeding rates compared to patients who receive clopidogrel. It is contraindicated in the setting of stroke and TIA, and it should be avoided in patients > 75 years of age or those weighing less than 60 kg, since these patients showed no clinical benefit in trials. There’s also a narrow spectrum of patients who are appropriate candidates for prasugrel. We usually don’t use it up-front in the setting of NSTE-ACS in patients undergoing invasive management or for those undergoing a more conservative approach. Nor is it recommended in patients likely to need a CABG. I’d just rather not think about all these nuances and stay away from this one.

And finally, we come to ticagrelor, or Brilinta. Ticagrelor is not a thienopyridine, rather it is a new class of agent that I won’t even try to pronounce (cyclopentyl-triazolopyrimidine). This agent directly inhibits the P2Y12 receptor without needing hepatic activation. This means that there is much less genetic and drug-drug interactions as compared to the other agents, especially clopidogrel. Some pros of this agent are that it achieves a higher and more consistent inhibition of platelet aggregation than both of the other two agents. It is reversible, unlike other agents, and has a rapid offset. It’s also been shown to have a reduction in ischemic event rates vs clopidogrel and has proven efficacy regardless of ACS treatment strategy. Something prasugrel is jealous of.

Some cons of this agent are that it is expensive and is dosed twice-daily. It can also cause dyspnea (up to 15% of patients) and it can also cause ventricular pauses. So, it should be avoided in patients at risk of bradycardia and other arrhythmias. Also, the benefit of ticagrelor over clopidogrel was limited to patients taking 75 – 100 mg of aspirin, so we have to make sure our patients are not discharged on higher aspirin doses when we use this agent.

In conclusion, remember that clopidogrel’s efficacy is affected by many things including genetics and drug-interactions. Its niche can be limited to patients receiving thrombolytics in centers without cath labs, or for those patients who come in on anticoagulation, such as warfarin or a DOAC, who then also need dual antiplatelet therapy. Prasugrel comes with too many nuances and warnings that I personally just can’t keep straight. For the most part, it seems that ticagrelor rules the roost for now due to its proven efficacy and indications of use in any ACS situation, keeping in mind that patients have to be on < 100 mg of aspirin (usually 81 mg in the US) and that it can cause dyspnea and ventricular pauses.

As always, thank you for your time. We recently hit a big milestone with over 10,000 downloads in over 50 countries! If you have anything you would like to add, or have topics for future episodes, please reach out to us on errxpodcast.com


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