Dyspnea Associated with Ticagrelor

Ticagrelor is an antiplatelet medication that is commonly used for a number of cardiovascular conditions.  Its mechanism is similar to that of antiplatelet medications clopidogrel and prasugrel in that it inhibits P2Y12 ADP receptors on platelets, preventing platelet activation and aggregation.  Ticagrelor is different from clopidogrel and prasugrel in that it binds reversibly to the receptor and, importantly, it is administered as the active compound.  This contrasts with clopidogrel and prasugrel which require metabolic activation by CYP450 enzymes and are therefore susceptible to drug interactions and altered activation in those with polymorphic CYP450 phenotypes (clopidogrel requires two CYP450 enzyme steps for

activation and prasugrel requires one CYP450 enzyme step).  Ticagrelor is used to reduce cardiovascular risk in patients with acute coronary syndrome (ACS), cerebrovascular accidents (CVA), transient ischemic attacks (TIA), and a history of myocardial infarction (MI).¹

 

Rates

Dyspnea secondary to ticagrelor use has been of interest for many years and was reported in large randomized controlled trials in different populations.  Rates of dyspnea are as high as 21% and data from some of the largest studies of ticagrelor are described in the table below (these four studies alone included more than 70,000 patients). ^2-5

 

Trial	Patient population	Dyspnea rates
		Ticagrelor	Comparator
PLATO (2009)	ACS	13.8%	7.8% (clopidogrel)
PEGASUS-TIMI 54 (2015)	MI (1 to 3 years ago)	18.9% (90 mg dose) 15.8% (60 mg dose)	6.4% (placebo)
SOCRATES (2016)	Acute CVA/TIA	6.2%	1.4% (aspirin)
THEMIS (2019)	Stable CAD plus T2DM	21.4%	7.3% (placebo)

 

Clinical presentation

It’s important to understand the characteristics of dyspnea secondary to ticagrelor as other dyspnea in these patient populations could be a concerning sign of untreated, undertreated, or new cardiovascular problems.  As such, being able to differentiate between the two would be helpful.

Dyspnea in general may be described as difficult or painful breathing, air shortage, or unsatisfied inspiration.  Dyspnea due to ticagrelor usually occurs in the first week of treatment (but can be for several weeks), has a sudden onset, and only lasts a minute or two before waning without any intervention.  During this time, the patient may experience fear, panic, and anxiety.  Intensity increases to a peak and then decreases within these minutes.  Severity is usually mild but can be severe. Onset of dyspnea tends to be about two hours after taking ticagrelor (when concentrations are at their peak) so paying attention to administration times may be helpful in working up the differential. A drop in oxygen saturation and bradycardia may occur at this time, but not necessarily.  Ticagrelor-induced dyspnea is not associated with a cough or any body position. ¹ 

 

Mechanism of dyspnea secondary to ticagrelor

There are two proposed mechanisms for how ticagrelor induces dyspnea and each is challenged with some uncertainty. ¹

1. Increase in extracellular adenosine.  Ticagrelor inhibits transporters that usually move adenosine into cells. Higher concentrations of extracellular adenosine then bind vagal C fibers on the bronchial wall and cause bronchial smooth muscle cell contraction, release of bronchoconstrictive mediators, and the sensation of dyspnea. 
• Some uncertainties of this hypothesis include that other medications that increase adenosine concentrations (e.g., dipyridamole) do not necessarily cause dyspnea.  Also, they’ve measured tissue concentrations of adenosine and some patients with ticagrelor-induced dyspnea do not have elevated levels of adenosine.  Last, they’ve analyzed the use of caffeine (an adenosine antagonist which could theoretically be protective against ticagrelor-induced dyspnea) and found it did not reduce dyspnea rates.
  
2. P2Y12 receptor.  Ticagrelor not only inhibits P2Y12 receptors on platelets but also on other cells, namely neurons and glial cells. Inhibiting P2Y12 here may stimulate the central chemoreflex system and elicit Cheyne-Stokes respiration (i.e., what seems to be dyspnea).   
• Some background here may explain why dyspnea occurs with ticagrelor but not other P2Y12 inhibitors like clopidogrel.  Recall that neurons and glial cells have nuclei (unlike platelets) so they can produce new P2Y12 receptors on their own.  Ticagrelor dosed twice a day (compared to daily clopidogrel) maintains near constant high concentrations at these cells so it continues to block the newly produced P2Y12 receptors throughout the day.  Alternatively, when using clopidogrel, new P2Y12 receptors are created at glial cells throughout the day but they are not inhibited because clopidogrel is no longer present in high enough concentrations.  Therefore, this lack of inhibiting new P2Y12 receptors with clopidogrel does not result in the same ill respiratory effects.
  

 

What to do if you suspect it 

 

While dyspnea was very common in the studies mentioned above, it was much less often the cause for medication discontinuation.  Medication discontinuation was more commonly due to bleeding than due to dyspnea, likely due to the generally mild, transient nature of the dyspnea.  Ultimately, ticagrelor-induced dyspnea is a diagnosis of exclusion and the workup for other causes of dyspnea should be followed (e.g., heart failure, asthma).  If not severe in nature, it is reasonable to continue ticagrelor and observe the patient for 3-4 days while evaluating other causes.  During this time, the severity of dyspnea may wane.  Counseling patients regarding the nature of this toxicity may be helpful in promoting long-term medication adherence.  Of the large studies mentioned above, premature discontinuation rates of ticagrelor overall were in the 20-30% range, potentially undermining the cardioprotective effects of this medication. ^1,6

 

Take home points:

• Ticagrelor commonly causes dyspnea with rates up to around 20% of patients.

• Symptoms are usually mild, lasting only a few minutes each, occurring 2 hours after dosing, and resolve within a week.

• As a diagnosis of exclusion, the workup for other causes of dyspnea should occur.

• In most cases, if symptoms are not severe, it is reasonable to continue treatment and observe the patient for a few days to a week.

   
  

References

1.  Krakowiak A, Kuleta J, Plech I, Zarębiński M, Wojciechowska M, Wretowski D, Cudnoch-Jędrzejewska A. Ticagrelor-Related Severe Dyspnoea: Mechanisms, Characteristic Features, Differential Diagnosis and Treatment. Clin Med Insights Case Rep. 2020.

2.  Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators; Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57.

3.  Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, Bengtsson O, Oude Ophuis T, Budaj A, Theroux P, Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, Murphy SA, Wiviott SD, Held P, Braunwald E, Sabatine MS; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015 May 7;372(19):1791-800.

4.  Johnston SC, Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, Held P, Jonasson J, Minematsu K, Molina CA, Wang Y, Wong KS; SOCRATES Steering Committee and Investigators. Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack. N Engl J Med. 2016 Jul 7;375(1):35-43.

5.  Steg PG, Bhatt DL, Simon T, Fox K, Mehta SR, Harrington RA, Held C, Andersson M, Himmelmann A, Ridderstråle W, Leonsson-Zachrisson M, Liu Y, Opolski G, Zateyshchikov D, Ge J, Nicolau JC, Corbalán R, Cornel JH, Widimský P, Leiter LA; THEMIS Steering Committee and Investigators. Ticagrelor in Patients with Stable Coronary Disease and Diabetes. N Engl J Med. 2019 Oct 3;381(14):1309-1320.

6.  Arora S, Shemisa K, Vaduganathan M, et al. Premature Ticagrelor Discontinuation in Secondary Prevention of Atherosclerotic CVD. J Am Coll Cardiol. 2019 May, 73 (19) 2454–2464.

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