INTRODUCTION
Acute coronary syndrome (ACS) is a leading cause of myocardial infarction in the world.
It is one of the major cause of mortality in the present lifestyle scenario and a
main reason for hospital admissions. A critical role in atherothrombosis is played
by platelets.[1] Antiplatelet agents are of great therapeutic value in thromboembolic
diseases.[2] Potent inhibitors of platelet function have been developed in recent
years, resulting in lowered rates of restenosis and thrombosis after angioplasty and
vascular stenting procedures.[1]
Aspirin has been the gold standard antiplatelet agent for the prophylaxis of myocardial
infarction and other thromboembolic events.[3] The thienopyridenes (clopidogrel, ticlopidine
and prasugrel) are another class of antiplatelet agents that inhibit adenosine diphosphate
induced platelet aggregation irreversibly via P2Y12 receptor located on the surface
of platelets.[4
5]
It has been seen that 1 in 3 ACS patient dies due to repeat MI despite intensive monitoring
and prompt treatment of cardiac instability, thrombolytic activity, acute invasive
interventions and dual antiplatelet therapy with aspirin and thienopyridines.[6] In
patients with ACS, the most commonly used thienopyridine is clopidogrel.[6] However,
it has some limitations. It causes irreversible inhibition of platelets and thus may
increase the risk of bleeding in patients who may require surgery/intervention. Moreover,
it requires hepatic conversion to an active metabolite resulting in delayed onset
of action and there is an interindividual variation in conversion rate due to pharmacogenomic
differences. The mean levels of inhibition of ADP-induced platelet aggregation with
clopidogrel are modest.[7] So, there is a need to have a new antiplatelet agent without
all these drawbacks. Ticagrelor is expected to confer better antiplatelet effects
to patients with ACS while being devoid of these demerits.
CHEMICAL STRUCTURE AND MECHANISM OF ACTION
Ticagrelor (formerly AZD140), a novel non-thienopyridine platelet P2Y12 receptor antagonist,
is the first oral agent in a new chemical class of cyclopentyl-triazolo-pyrimidines
(CPTP). Exploration of structure–activity relationships showed affinity-increasing
property of substituents in the 2nd position of the ATP adenine ring and stability-increasing
properties of β, γ-methylene substitutions in the triphosphate. The drug development
program with ATP analogs led to the identification of several potent selective P2Y12
antagonists with short half-life and requiring intravenous (IV) administration like
cangrelor. Subsequent modifications by elimination of phosphate group and changes
in the core purine and sugar moiety resulted in identification of the first selective
and stable non-phosphate P2Y12 antagonist AR-C109318XX. Further refinement to improve
oral bioavailability resulted in development of ticagrelor, the first CPTP to be developed
clinically.[7]
Ticagrelor selectively blocks the platelet P2Y12 receptor by interacting with a binding
site different from ADP (non-competitive inhibition) and thus, inhibits the prothrombotic
effects of ADP. Unlike thienopyridines, the binding of ticagrelor to P2Y12 receptor
is reversible.[8
9]
PHARMACOKINETICS AND DOSAGE
Ticagrelor is absorbed quickly from the gut, with a bioavailability of 36%. The peak
plasma levels are reached in 1.5-3.0 hours. Its half-life is approximately 12 hours.
The antiplatelet effect is low at 48 hours after the last dose.[9
10] Ticagrelor is predominantly metabolized by CYP3A4 and to some extent by CYP3A5.
ARC124910XX is an active metabolite of ticagrelor, but the parent compound is responsible
for the majority of the antiplatelet effect.[9
11] Elimination is through hepatic metabolism. No dose adjustment is required in patients
with renal impairment.
The recommended oral dose of ticagrelor is 180 mg (loading dose) followed by a dose
of 90 mg twice daily.[12
13] A number of trials have been conducted to study the clinical efficacy of ticagrelor
in preventing thrombotic events in patients with ACS.
CLINICAL TRIALS
Onset/Offset trial
The ONSET/OFFSET trial, a phase II study, evaluated the timing of the antiplatelet
effect of ticagrelor versus clopidogrel in patients with stable coronary artery disease.
A total of 123 patients were randomized to receive ticagrelor 180 mg loading dose
followed by 90 mg twice daily or clopidogrel 600 mg loading dose followed by 75 mg
daily for 6 weeks. Aspirin 75-100 mg daily was given to all patients. At all time
points 0.5, 1, 2, 4, 8 and 24 hours after loading dose and at 6 weeks, ticagrelor
had a significantly greater inhibition of platelet aggregation (IPA). The offset of
ticagrelor action was also faster as evidenced by a comparable IPA result for ticagrelor
at day 3 to that of clopidogrel at day 5. This study demonstrates that ticagrelor
has faster onset and offset action compared to clopidogrel due to its reversible nature.[11
12]
Disperse trial
In DISPERSE study, a phase II trial, 200 patients with atherosclerosis were randomized
to receive either ticagrelor (doses of 50, 100 or 200 mg twice daily or 400 mg once
daily) or clopidogrel (75 mg once daily) for 28 days in addition to 75-100 mg of aspirin
once daily.[8] This trial demonstrated nearly complete inhibition of ADP-induced platelet
aggregation with ticagrelor 100 mg, 200 mg twice daily and 400 mg once daily doses
as compared to clopidogrel.[8
9] This trial was followed by a metacentric DISPERSE-2 trial to analyze the safety
and efficacy of ticagrelor in 990 patients with non-ST elevation ACS. The patients
in this trial were randomized to receive ticagrelor 90 mg or 180 mg twice daily or
clopidogrel 300 mg loading dose plus 75 mg once daily for up to 2 weeks. It is to
be noted that the 90 mg and 180 mg doses of ticagrelor used in DISPERSE-2 were reformulations
of the 100 mg and 200 mg doses used in DISPERSE. This study demonstrated that 90 mg
ticagrelor twice daily possess similar safety and efficacy compared to clopidogrel
but ticagrelor 180 mg twice daily have poorer safety compared with clopidogrel.[8
9
11]
Respond trial
This was a randomized, double-blind, double-dummy, crossover trial, which was conducted
on 98 patients with stable coronary artery disease. This study included both clopidogrel
responders and non-responders. The RESPOND trial revealed the mean IPA increase of
26% in clopidogrel responders switching from clopidogrel to ticagrelor but 24% mean
IPA decrease switching from ticagrelor to clopidogrel. Thus, it was concluded that
clopidogrel non-responders and responders exhibit superior platelet inhibition with
ticagrelor therapy.[8
9]
Plato trial
The PLATO study is the largest phase III trial, which started in October, 2006 and
ended in March, 2009. It was a multicentered or multicentric, double-blind, randomized
trial in patients with ACS comparing 2 treatment strategies: ticagrelor (180 mg loading
dose, 90 mg twice daily thereafter) and clopidogrel (300 to 600 mg loading dose, 75
mg daily thereafter) with a goal to evaluate the impact of a more potent platelet
inhibitor for the prevention of cardiovascular events. In this study, 18,624 patients
admitted to the hospital with ST elevation myocardial infarction (STEMI) and non-ST
elevation myocardial infarction (NSTEMI) were evaluated. At 12 months, the primary
end point, that is, a composite of death from vascular causes, MI or stroke had occurred
in 9.8% of patients receiving ticagrelor compared with 11.7% of those receiving clopidogrel.
PLATO showed that treatment with ticagrelor as compared with clopidogrel in patients
with ACS significantly reduced the mortality from vascular causes, myocardial infarction
and stroke.[4
10]
Pegasus-timi 54 trial
It is an ongoing trial that aims to compare long-term treatment with ticagrelor plus
acetylsalicylic acid (ASA) to ASA alone in reducing the composite end point of cardiovascular
death, non-fatal MI and non-fatal stroke.[6
11
12]
INDICATIONS
Ticagrelor co-administered with aspirin is indicated in ACS (unstable angina, both
NSTEMI and STEMI) and in the patients who are to be managed with percutaneous coronary
intervention (PCI) or coronary artery by-pass graft (CABG) for the secondary prevention
of thrombotic events (cardiovascular death, myocardial infarction and stroke).[6
14]
ADVERSE EFFECTS
Ticagrelor is generally well tolerated.[9] Headache, hypotension, epistaxis, bradyarrythmias,
ventricular pauses (not associated with clinical symptoms), elevated liver enzymes,
raised serum creatinine and elevated uric acid levels have been reported with ticagrelor
in some patients.[6
7] Dyspnea was reported in some of the patients, which was mild to moderate in nature.
Bleeding is the most common adverse effect seen with ticagrelor. The bleeding events
have been reported in the form of subcutaneous/dermal bleeding, gastrointestinal hemorrhages
and urinary tract bleeding.[6
11
13
14] The monitoring of hemoglobin concentration and renal function is recommended with
ticagrelor therapy.[6]
CONTRAINDICATIONS[11
14]
Hypersensitivity to ticagrelor.
Active pathological bleeding such as peptic ulcer.
History of intracranial hemorrhage.
Moderate to severe hepatic impairment.
DRUG INTERACTIONS
Ticagrelor is a moderate inhibitor of CYP3A4, CYP2C9, CYP3A5 and CYP2D6.[6] Ticagrelor
and its major metabolite are weak p-glycoprotein substrates and inhibitors. Digoxin
levels need to be monitored when given along with ticagrelor, the latter being a p-glycoprotein
inhibitor.[6
14] Antiplatelet drugs and statins are commonly administered together in patients
with cardiovascular diseases. Ticagrelor when given with simvastatin and lovastatin
increases their serum concentration as they are metabolized by CYP3A4. So, simvastatin
and lovastatin in doses >40 mg should be avoided with ticagrelor.[14
15] Ticagrelor should be avoided in patients on CYP3A4 inhibitors (ketoconazole, clarithromycin,
nefazodone, ritonavir and atazanavir) and CYP3A4 inducers (rifampicin, dexamethasone,
phenytoin, carbamazepine and phenobarbital).[14]
SUMMARY
Ticagrelor possesses many desirable characteristics as compared to the thienopyridines
and was approved by European Union in December, 2010.[15] Ticagrelor got FDA approval
in July, 2011 for clinical use in ACS. It is not available in India yet. As compared
to clopidogrel, ticagrelor has a faster and stronger antiplatelet effect along with
a greater clinical efficacy with a comparable rate of bleeding. It has been indicated
to be used with low dose aspirin (aspirin dose not exceeding 100 mg) as it loses its
efficacy when administered with high dose aspirin.
Ticagrelor at present is in use for ACS but may also offer promising results in broader
clinical scenarios, like stroke, in the future, based on ongoing trials.