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Old doc, new drug: Ticagrelor


Casey Parker


5/11/2018 11:53:33 AM

Dr Casey Parker examines the use of this difficult-to-pronounce drug.

‘I like to call [ticagrelor] “tiger claw” and everyone around me seems to know what I am talking about,’ Dr Parker explained.
‘I like to call [ticagrelor] “tiger claw” and everyone around me seems to know what I am talking about,’ Dr Parker explained.

We all love to interfere with the clotting cascade in modern medicine, and this is a new way to do so – with yet another practically unpronounceable new drug.
 
Ticagrelor – pronounced Ti-CAG-re-lor – is the latest in the family of drugs [cyclopentyltriazolopyrimidines … you can forget that word immediately] that stop clots and start bleeding.
 
I like to call it ‘tiger claw’ and everyone around me seems to know what I am talking about.
 
So, what is it?
Technically, it is a P2Y12 ADP receptor blocker. That means 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.
 
Based on that, 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 ticagrelor in combination with aspirin in order to get it to actually work. So there, right off the bat, we have a combination in play.
 
You may already be familiar with clopidogrel. This is also a P2Y12 ADP inhibitor, but is actually a prodrug. Clopidogrel undergoes conversion to the active metabolite via the CYP2C19 enzyme in the liver (do all of these coded names make your corneas hazy?)
 
Unfortunately, about 15–20% of the population is deficient in this enzyme and thus may get little or no actual action out of a dose of clopidogrel. There is data to suggest that if you lack the enzyme you are 3–4 times more likely to have a serious cardiovascular event, or even die.
 
So you may like to think of ticagrelor as the substitute for clopidogrel without the genetic lottery.
 
When studied head-to-head in 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 towards more serious bleeds (brain ones), as well as and more minor bleeds. This is really just something we should all expect when prescribing bleed-y drugs.
 
It should be noted, 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 (ie greater than 150 mg/day), 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 is used for patients who have had an acute myocardial infarction (STEMI or non-STEMI) or unstable angina. It is the preferred drug for many cardiologists after placing a stent, when they usually want the patient to remain on ticagrelor for around a year.
 
Many cardiologists get very nervous about placing stents in patients whom they feel are unlikely to comply with a P2Y12 ADP blocker. This is where GP counselling and support with pharmacological help can be especially useful.
 
The detail
Ticagrelor is usually initiated at a loading dose of 180 mg (two 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 five days prior to surgery. There are no ‘reversal agents’ to save the day with these drugs.
 
Common adverse effects include:

  • dyspnoea (14% in PLATO) – which may be a problem for the patients with chronic obstructive pulmonary disease (COPD), asthma or other lung diseases
  • ventricular pauses – yes, about 5% of patients’ heart stopped for three seconds or more in the first week of treatment. That sounds bad. If symptomatic, this would likely be a problem for many folks. That means ticagrelor is not a good option for patients with underlying bradycardia or blocks.
In addition, minor bleeding is common, and 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. For example, 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?)
 
Long term
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. Hopefully, more data will aid us in the future.
 
So, in short, that’s what you really need to know about ticagrelor.



clopidogrel drug mechanisms Ticagrelor



Dr Barbara Elisabeth Uhlenbruch   6/11/2018 8:42:40 AM

Written in a way that I get it immediately and am likely to remember . Thanks!


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