Overview:
Since then, dual antiplatelet therapy has been considered the standard of treatment. Dual antiplatelet therapy with Aspirin and P2Y12 receptor antagonist Clopidogrel has shown significant benefits to Aspirin alone. Clopidogrel had an antiplatelet response with drug interactions, and Prasugrel needs to activate by metabolizing. So, a new antiplatelet drug Ticagrelor was approved by FDA.
Ticagrelor is an antiplatelet medicine. It is a P2Y12 platelet inhibitor used in heart disease patients to prevent any heart attack or stroke. It also prevents myocardial infarction and cardiovascular death. It got its approval from FDA (Food and Drug Administration) on 20 July 2011. It works by blocking the platelets from sticking together and preventing them from forming harmful clots. As a result, it keeps the blood flowing smoothly throughout the body.
Indications of Ticagrelor:
Ticagrelor is a P2Y12 platelet inhibitor indicated for patients with a history of acute coronary syndrome or myocardial infarction to decrease the risk of cardiovascular death, myocardial infarction, and stroke. It is used for at least the first twelve months in acute coronary syndromes.
It also decreases the rate of stent thrombosis in patients who are stented for acute coronary syndrome treatment.
Dosage and Administration:
Dose Strength: 60 mg and 90 mg.
Dose Form: Tablets.
Administration: Start the dose with 180 mg for the acute coronary syndrome. Continuing the dosage with 90 mg twice daily in the first year, followed by 60 mg twice daily. Ticagrelor is given along with 75 mg to 100 mg of maintenance dose of Aspirin.
Contraindications:
Ticagrelor is contraindicated in:
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The patient has a history of intracranial hemorrhage.
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The patient with active pathological bleeding.
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If the patient is allergic to the Ticagrelor or shows a hypersensitivity reaction to the drug.
Warning and Precautions:
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Dyspnea: The patients who use the Ticagrelor have expressed the symptoms of dyspnea in the studies performed.
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Severe Hepatic Impairments: The patient with severe hepatic impairments should avoid using Ticagrelor, as their condition may show an increase in serum concentrations of Ticagrelor.
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Bradyarrhythmias: There are chances of developing bradyarrhythmias with the use of Ticagrelor. Patients reported with sinus syndrome, bradycardia-related syncope, and those who are not protected by the pacemaker should avoid using Ticagrelor.
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Bleeding: Ticagrelor is an antiplatelet that works by inhibiting platelet functions and thus increases the risk of bleeding. So, try to control the bleeding without discontinuing the Ticagrelor.
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Co-Administration of Aspirin for Maintenance Dose: The maintenance dose given along with Ticagrelor can decrease the effectiveness of Ticagrelor if given above 100 mg of Aspirin- njj .
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Discontinuation of Ticagrelor: On discontinuation of Ticagrelor, there can be a risk of myocardial infarction, stroke, or death. If Ticagrelor is temporarily discontinued, it should soon be started without interruption. Ticagrelor is interrupted five days before surgery because it has a significant risk of bleeding but restarts soon after hemostasis.
Special Considerations:
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Pregnancy: There are no conclusive results of the studies of Ticogrelor on pregnant women. However, the use of Ticagrelor on pregnant women should be cautious because its use on animals (rats) has adverse outcomes.
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Nursing Mothers: There is no clear picture of the Ticagrelor being excreted in breast milk, although it is excreted in rat's milk. Some patients should either go for Ticagrelor use or breastfeeding; both can not be carried together.
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Pediatric Use: No results have been determined related to the safety and effectiveness of Ticagrelor in child patients.
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Geriatric Use: No determined results related to Ticagrelor's safety and effectiveness on older patients are present.
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Hepatic Impairment: Avoiding the use of Ticagrelor in severe hepatic impairment patients. Cautious use of Ticagrelor in the patient with moderate hepatic impairments. No dosage variations are required in patients who are mildly impaired.
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Renal Impairments: No dosage adjustment is required in the renal-impaired patient.
For Patients:
What Is the Use of Ticagrelor?
Ticagrelor is used to prevent severe conditions like a heart attack or stroke, especially in patients with heart diseases or acute coronary syndrome that can lead to other life-threatening severe conditions. It is also used in patients with coronary stent treated for acute coronary syndrome.
Why Is Ticagrelor Prescribed for These Conditions?
Ticagrelor is an antiplatelet medicine that works by inhibiting platelets from collecting and clot-forming so that no heart attack or stroke can occur. And blood keeps on flowing smoothly through the blood vessels.
How to Use Ticagrelor?
Ticagrelor comes in tablet form. It is taken orally, usually with or without food, twice daily. It is recommended to take the tablet at the same time every day. If it is unable to swallow by the patient, then it can be crushed and mixed with water. But drink the mixture immediately, and again refill the glass with water, stir, and drink it. It can be taken by nasogastric tube but requires a doctor to explain and use it. The patient should consult the doctor before taking the dose, as the chances of having a heart attack increase. And if the patient has a stent, the chances of developing a blood clot increase.
What Are the Precautions Before Using Ticagrelor?
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The patient should inform the doctor about the allergic reaction to Ticagrelor if it develops.
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Inform the doctor about any medication the patient is taking.
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The patient should inform the doctor about the irregular heartbeat that is not cured by a pacemaker or any lung diseases like asthma or chronic pulmonary heart disease (COPD).
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The patient should inform if the patient is pregnant or breastfeeding the child.
What if the Regular Dose Got Missed?
If the regular dose of the patient got missed, then the patient should take the dose soon on remembering, or if the next dose is near, the patient should go for the next regular dose by skipping the previous one instead of taking the double dose.
What Are the Side Effects of Ticagrelor?
Side effects are:
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Dizziness.
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Nausea.
Adverse effects are severe effects that require medical attention.
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Shortness of breath.
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Chest pain.
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Irregular heartbeat.
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Rash.
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Swelling of face, throat, tongue, lips, and eyes.
How to Store and Dispose of the Ticagrelor?
The medicine Ticagrelor is kept out of reach by children in tight containers so that the children cannot open them easily.
The unrequired medicine is disposed of in a special way, instead of flushing it in a toilet or throwing it outside. In addition, special take-back programs are present to dispose of unrequired medicine to ensure that no pet, children, or people unknowingly intake the medicine.
What Happens if an Overdose of Ticagrelor Occurs?
If Ticagrelor overdoses, then symptoms like
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Bleeding.
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Vomiting.
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Nausea.
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Diarrhea.
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Irregular heartbeat.
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Seizures.
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Troublesome breathing.
For Doctors:
Ticagrelor:
Ticagrelor is an ADP derivative which is a P2Y12 receptor antagonist. It belongs to a class of antiplatelet agents named cyclopentyltriazolopyrimidine, an inhibitor of platelet activation and aggregation mediated by the P2Y12ADP- receptor. Therefore, it is not a prodrug like Clopidogrel. Its chemical formula is C23H28F2N6O4S. It has a molecular weight of 522.57.
What Are the Indications of the Ticagrelor?
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Ticagrelor is indicated to decrease the risk of cardiovascular death, stroke, and myocardial infarction in patients suffering from acute coronary syndrome or with a history of myocardial infarction.
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It is also indicated in patients treated with stents to decrease their stent thrombosis.
Mechanism of Action of Ticagrelor:
The P2Y12 receptor combines with Gi2 and Gi proteins that prevent adenylyl cyclase. Gi protein acts by signaling and activating PI3K, Akt, and potassium channels. The down effects of all these activate hemostasis and platelet aggregation.
Ticagrelor binds reversibly and non-competitively to the P2Y12 receptor at the site that is away from the endogenous agonist adenosine diphosphate (ADP). It interacts with the ADP receptors to prevent signal transduction and platelet activation. As Ticagrelor is an antagonist of the P2Y12 receptor, it inhibits these activities.
What Are the Pharmacodynamics of Ticagrelor?
Ticagrelor is a P2Y12 receptor antagonist that inhibits the formation of clots or thrombosis, thus decreasing the risk of myocardial infarction and stroke. It has a moderate duration of action with a wide therapeutic index, as high single doses are tolerable.
What Are the Pharmacokinetics of Ticagrelor?
Absorption:
Ticagrelor is taken with or without food. It forms its major metabolite in 2.5 hours. The absorption of the high-fat meal has no effects on Ticagrelor. Ticagrelor is only 36 % bioavailable.
When given as a crushed or nasogastric tube into the stomach, it is bio-equivalent to a whole tablet because its bioavailability reaches around 90 %, gets absorbed in one hour, and forms a significant metabolite in two hours.
Distribution:
The distribution of Ticagrelor is 88 L, and it binds to plasma proteins with 99 %.
Metabolism:
CYP3A4 is an enzyme that metabolizes the Ticagrelor and forms a major metabolite. Systemically, it is present in nearly 30 to 40 % of Ticagrelor. Ticagrelor and its active metabolites are weak P-glycoprotein substrates and inhibitors.
Excretion:
Ticagrelor is excreted by hepatic metabolism. The radioactive recovery is 84 %, 58 % in feces, and 26 % in urine. The primary route is biliary secretion. The half-life of Ticagrelor is 7 hours and 9 hours for active metabolites.
What Is the Nonclinical Toxicology of Ticagrelor?
Carcinogenesis: Ticagrelor has shown carcinogenic results in studies done on rats; the reports showed that female rats are more affected than male rats by increasing the dosage.
Mutagenesis: No demonstrations are presently related to Ticagrelor's mutagenic effects.
Impairment of Fertility: Ticagrelor has no effects on male fertility, but female rats have shown variable results related to their estrous cycles.
What Is the Dosage and Administration of Ticagrelor?
Dosage Forms: Ticagrelor is available in the form of tablets.
Dosage Supplied: The dosage is supplied as a round, biconvex, pink, film-coated tablet.
Dosage Strength: It is available in 60 mg and 90 mg.
Administration:
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It is initiated with a 180 mg loading dose, administered twice daily as 90 mg. But it is given in the first year after acute coronary syndrome. After one year, the dosage of 60 mg is given twice daily.
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Ticagrelor is co-administered with 75 to 100 mg of Aspirin.
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Patients who cannot swallow the drug can crush or mix it with water and drink it. The mixture can also administer by using nasogastric tubes.
Drug Interaction:
Potent CYP3A Inhibitors: They increase Ticagrelor exposure, and thus, the chances of dyspnea, bleeding, and other effects also increase. Therefore, strong CYP3a inhibitors are to be avoided with Ticagrelor.
Strong CYP3A Inducers: They reduce the Ticagrelor exposure and thus decrease the efficacy of the Ticagrelor. Avoiding the use of Ticagrelor with CYP3A inducers like Rifampicin and Phenytoin.
Aspirin : The use of Aspirin above 100 mg decreases the effectiveness of Ticagrelor.
Simvastatin and Lovastatin: The use of these drugs more than 40 mg with Ticagrelor is avoided because Ticagrelor increases serum concentration levels.
Digoxin: Ticagrelor blocks the P-glycoprotein transporter, and the use of Digoxin causes changes in the Ticagrelor therapy.
Overdosage:
There is no known therapy to reverse the adverse overdosage effects of Ticagrelor. Bleeding is the main effect that usually occurs on overdosage. On bleeding, supportive measures are necessary to be taken.
Platelet transfusions are performed in patients with bleeding symptom overdosage.
Gastrointestinal effects of overdosage - nausea, vomiting, and diarrhea.
Clinical Studies:
- PLATO: Acute coronary syndrome and secondary prevention after myocardial infarction or PLATO was a double-blinded, randomized study comparing Ticagrelor (N=9333) with Clopidogrel (N=9291) along with Aspirin as standard therapy in the patients with the acute coronary syndrome. The study's primary endpoint was the patient's first occurrence of cardiovascular death or non-fatal stroke. All the patients received Ticagrelor as 180 mg of a loading dose followed by a 90 mg maintenance dose given twice daily. And the patient receiving Clopidogrel for six months was given 300 mg. Both these were co-administered with 75 to 100 mg. The patients were treated for six months to twelve months. 43 % were patients with more than 65 % of age, and 15 % were patients with more than 75 % of age. Eleven thousand two hundred eighty-nine patients having stent during the PLATO have a lower risk of stent thrombosis than earlier with Ticagrelor than Clopidogrel.
Results: On comparison done in Canada and North America, there is a lesser effect among North America. However, the statical test comparison is statistically significant (p=0.009) and exact tests for cardiovascular death and non-fatal myocardial infarction. But the baseline and procedural differences between the United States and non-United States have been examined to determine if they had any regional differences, except Aspirin maintenance dose.
Aspirin Maintenance Dose: PLATO used Aspirin as a maintenance dose in different sites in and outside the United States. 8 % used it in the non-United States with above 100 mg and 2 % above 300 mg; in the United States, 57 % received above 100mg and 54 % above 300 mg. But overall, results presented that the use of Ticagrelor with a low maintenance dose of Asipirn has shown similar results everywhere. The other higher doses have not established the benefits in the patients because above 100 mg reduces the effectiveness of the Ticagrelor.
- PEGASUS: Random, double-blind, placebo-control, and parallel studies in 21162 patients with two doses of Ticagrelor, either 90 mg given twice daily or 60 mg given twice daily, and a maintenance dose of 75 to 100 mg Aspirin in patients of myocardial infarction. The study's primary endpoint was the first occurrence of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Patient above 50 years was also included. A patient on dialysis or anticoagulants or had any gastrointestinal or intracranial hemorrhage was excluded. Patients were treated for 12 months to 48 months.
Results: Both results (60 mg or 90 mg of Ticagrelor) were better than the Aspirin alone in reducing the incidence of cardiovascular death, myocardial infarction, and stroke. The risk reduction after using Ticagrelor and the Aspirin alone was 1.27 % in 60 mg Ticagrelor and 1.19 % in 90 mg Ticagrelor. The efficacy profile of the two was the same, with the lower doses having a lower risk of bleeding and dyspnea.
