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Old Doc, New Drug: Ticagrelor

We all love to interfere with the clotting cascade in modern medicine, and this is a new way to do so!  Yet another unpronounceable new drug.  Ti-CAG-re-lor  is the latest in the family of drugs [cyclopentyltriazolopyrimidines.. forget that word immediately ] that stop clots and start bleeding.  I like to call it “tiger claw” and everyone around seems to know what I am talking about.

So what is it?

Technically, it is a P2Y12 ADP receptor blocker.  What that means is that it interferes with the mechanics of platelet activation and aggregation.  So it reduces the formation of clots in the final phase of the process. So you might think that it is a substitute for good old-fashioned aspirin.  They both inhibit platelets right?  Well, no.  In fact, you must use tiger-claw in combination with aspirin in order to get it to actually work. So there, right off the bat, we have a combination in play.

Now, you may already be familiar with CLOPIDOGREL.  This is also P2Y12 ADP inhibitor but is actually a prodrug.  Clopidogrel undergoes conversion to the active metabolite via the CYP2C19 enzyme in the liver (do all these coded names make your corneas hazy?)  Unfortunately, about 15 – 20% of the population is deficient in this enzyme and so may get little or no actual action out of a dose of clopidogrel.  There is data to suggest that if you lacked the enzyme you were 3 – 4 times more likely to have a serious cardiovascular event or die!  So you may like to think of TICAGRELOR as the substitute for clopidogrel without the genetic lottery.

When studied head-to-head (read the PLATO trial) the ticagrelor/aspirin combination was better than the clopidogrel/aspirin in preventing cardiovascular events (MI, CVA).  However, in the inevitable yin-yang of coagulation fiddling the more efficacious drug also tended to cause more bleeding.  There was a trend to more serious bleeds (brain ones) and more minor bleeds.  This is really just something we should all expect when prescribing bleedy drugs. It should be noted that subsequent evidence that has come out in recent times has been less enthralling – the benefits of ticagrelor were not replicated in some populations.

There is a bit of a paradox here. It is tricky to balance the benefits of ticagrelor over clopidogrel.  Ticagrelor mandates the concomitant use of aspirin.  Whereas clopidogrel is often used in patients who are intolerant of aspirin.  Even weirder, if higher dose aspirin is used (i.e. greater than 150 mg/day) then the benefits of ticagrelor seem to disappear… if you know why please let me know!

Annoyingly, ticagrelor is dosed twice daily.  This is a bit of a problem for a lot of patients, especially when you consider that most other agents in this area are once daily. One wonders if the PLATO trial superiority will be maintained in the “real world” as a result of the dosing requirements.

If you are a GP, then you will most likely not be the one initiating ticagrelor.  It used for patients who have had an acute myocardial infarction (STEMI or non-STEMI) or unstable angina.  It is the preferred drug for a lot of Cardiologists after placing a stent.  They usually want the patient to remain on ticagrelor for around a year after stents are inserted.  Many Cardiologists get very nervous about placing stents in patients whom they feel are unlikely to comply with a P2Y12 ADP blocker. This is really where GP counselling and support with pharmacology help can be super useful.

Having said that, there is no evidence for either efficacy or safety in patients taking ticagrelor for more than 12 months.  It seems to be a scenario where you need to balance risks against unknown benefits for your patient.  Good luck! Hopefully, more data will aid us in the future.

So here is what you really need to know.

Ticagrelor is usually initiated at a loading dose of 180 mg (2 pills) and then continued at 90 mg twice a day.  It should be combined with 75 – 100 mg of aspirin per day.

Ticagrelor has a short clinical half-life, so it can be discontinued if bleeding occurs or patients are undergoing procedures. The info sheet still suggests cessation 5 days prior to surgery.  There are no “reversal agents” to save the day with these drugs.

The common adverse effects include:

  • dyspnoea (14% in PLATO) which may be a problem for the patients with COPD, asthma or other lung diseases.
  • Ventricular pauses! Yes, about 5% of patients’ heart stopped for 3 seconds or more in the first week of treatment.  That sounds bad.  If symptomatic, this would likely be a problem for many folks.  Ticagrelor is not a good option for patients with underlying bradycardia or blocks.
  • Minor bleeding is common.  Skin, nose and gastrointestinal bleeding were all reported as we would expect.

Interactions of note:

  • CYP3A4 enzyme inhibitors lead to more drug in your blood and more bleeding eg. ketoconazole, clarithromycin, verapamil and of course… grapefruit juice (does anyone actually drink that?)
  • Simvastatin seems to result in more muscle issues when used with ticagrelor… choose another option?

OK, that is another episode of Pharmacology for Phools.  Let me know what you want to explore in upcoming articles.

Casey

 

Comments

  1. Great article.

    In the UK, ticagrelor now has approval for use for up to 3 years after the initial event or stent.

    So we are dropping the dose down to 60mg bd after 12 months, and continuing for 2 more years. This is only in selected patients, thought to gain most, eg multi vessel disease, older etc.

    Dr PJ McNally (MRCGP).

  2. Georgina Gibson says:

    Thanks….very helpful!

  3. Christine says:

    Most of our use has been in patients where there was a concern re: possible need for rescue CABG (due to much shorter half life), although CYP2C19 deficiency is very common in some ethnic groups (e.g. Japanese).

    Regarding the high aspirin doses – I was always taught that higher doses gave progressively more COX-2 effect (prostacyclin inhibition = pro-coagulant) than COX-1 effect (thromboxane A2 inhibition = anticoagulant), although I’ve always thought the upper dose limit for cardiac efficacy was higher than that (more in the range of 2-3mg/kg).

    Regarding reversal, there is some consensus recently with clopidogrel at least for surgery, which has a short half life but an irreversible effect. For normal platelet count, 25% function recovery at 48 hours usually means adequate haemostatic effect. For more urgent surgery, platelet transfusion to increase count by ~100 (i.e. what you’d be happy with as a minimum number) seems to be adequate.

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