Critical appraisal of ticagrelor in the management of acute coronary syndrome

Figures & data

Figure 1 Adenosine diphosphate (ADP) binds to the P2Y₁₂ receptor. This binding results in activation of the platelet which causes a conformational shape change, activation of the glycoprotein (GP) IIb/IIa receptors, and platelet aggregation. Ticagrelor binds at a site on the P2Y₁₂ receptor that is separate from the ADP binding site and produces a non-competitive inhibition, while the thienopyridines, clopidogrel and prasugrel, bind directly to the ADP binding site on the P2Y₁₂ receptor permanently blocking this site. Antiplatelet agents that block the P2Y₁₂ receptor have complementary effects with aspirin in terms of platelet inhibition because their mechanism of action is different than that of aspirin, which blocks cyclo-oxygenase-1 causing a decrease in thromboxane A2.

Abbreviations: 5HT, 5-hydroxytryptamine; α, alpha granules; ™, dense granules; ADP, adenosine diphosphate; ATP, adenosine triphosphate; COX-1, cyclo-oxygenase-1; GP, glycoprotein; TPα, thromboxane A2 receptor; TxA2, thromboxane A2.

Figure 2 Chemical structures of clopidogrel, prasugrel, ticagrelor, and adenosine.

Table 1 Comparison of P2Y₁₂ receptor inhibitors^{15,20,24,26,58}

Drug	Bioactivation	Receptor binding	Maximum IPA (%)*	Time to maximum IPA (hours)*	Half-life of active drug (hours)	Offset of antiplatelet action (days)†
Ticagrelor	No	Reversible	80–90	2–4	8–12	3
Prasugrel	Yes, one step P-450 activation	Irreversible	75–80	2–4	7§	5–7
Clopidogrel	Yes, two step P-450 activation	Irreversible	30–50	4–8	0.5§	5–7

* Notes: After a loading dose;

† time to achieve platelet aggregation of ≤20%;

§ pharmacologic effects are much longer due to irreversible receptor binding.

Abbreviation: IPA, inhibition of platelet aggregation.

Figure 3 Hazard ratios and 95% confidence intervals (in parentheses) for the PLATO study population with regards to the primary efficacy endpoint subdivided by daily aspirin dosage and geographic region. Daily dosages of aspirin > 300 mg were associated with a blunting of the benefit of ticagrelor, whereas dosages < 100 mg were associated with benefit of ticagrelor compared to clopidogrel. This finding was seen regardless of geographic region, but was most pronounced in the United States population which tended to use higher daily dosages of aspirin compared to the rest of the world.³⁵

Note: *Insufficient data in the United States population.

Table 2 Nonhemorrhagic side effects observed with ticagrelor in PLATO^20,28

	Ticagrelor (n = 9235)	Clopidogrel (n = 9186)
Dyspnea	13.8%	7.8%
Headache	6.5%	5.8%
Cough	4.9%	4.6%
Dizziness	4.5%	3.9%
Nausea	4.3%	3.8%
Atrial fibrillation	4.2%	4.6%
Hypertension	3.8%	4.0%
Non-cardiac chest pain	3.7%	3.3%
Diarrhea	3.7%	3.3%
Back pain	3.6%	3.3%
Hypotension	3.2%	3.3%
Fatigue	3.2%	3.2%
Chest pain	3.1%	3.5%
Gynecomastia	0.23%	0.05%
Increase in serum creatinine > 50%	7.4%	5.9%
Increase in serum uric acid from baseline	0.6 mg/dL	0.2 mg/dL

Note: Numbers are represented as percentage of patients unless stated otherwise.

Abbreviation: PLATO, PLATelet inhibition and patient Outcomes.

Table 3 Practical considerations when comparing clopidogrel, prasugrel, and ticagrelor

	Clopidogrel	Prasugrel	Ticagrelor
Indication(s)	ACS; recent MI, stroke, or established peripheral arterial disease	ACS with PCI	ACS
Dosing frequency	Once daily	Once daily	Twice daily
Concomitant aspirin dosage	75–325 mg/day	75–325 mg/day	≤100 mg/day
Pharmacogenomic variability in antiplatelet effect?	Yes	No	No
Contraindications other than active bleeding or drug hypersensitivity	None	Prior transient ischemic attack or stroke	Prior intracranial hemorrhage, severe hepatic impairment
Interaction with proton pump inhibitors?	Possible	No	No
AWP cost/30 days*	$222.55	$222.16	$265.13
UNMH cost/30 days*	$174.76	$174.45	N/A

* Note: Prices are expressed as United States dollars.

Abbreviations: ACS, acute coronary syndrome; AWP, average wholesale price; MI, myocardial infarction; N/A, not available; PCI, percutaneous coronary intervention; UNMH, University of New Mexico Hospital.

Table 4 Bleeding rates in the PLATO and TRITON-TIMI 38 trials based on TIMI criteria^8,28

	PLATO			TRITON-TIMI 38
	Ticagrelor	Clopidogrel	P value	Prasugrel	Clopidogrel	P value
CABG-related major bleeding*	5.3	5.8	0.32	13.4	3.2	<0.001
Non-CABG-related major bleeding*	2.8	2.2	0.03	2.4†	1.8†	0.03
Major or minor bleeding*	11.4	10.9	0.33	5.0	3.8	0.002
Major bleeding, study criteria	11.6†	11.2†	0.43	NA	NA	NA

* Notes: According to TIMI criteria;

† primary safety endpoint; numbers are expressed as percentage of patients.

Abbreviations: NA, not applicable; PLATO, PLATelet inhibition and patient Outcomes; TIMI, Thrombolysis in Myocardial Infarction.

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