|Trade names||Brilinta, Brilique, others|
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|Elimination half-life||7 hrs (ticagrelor), 8.5 hrs (active metabolite AR-C124910XX)|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||522.57 g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Ticagrelor, sold under the brand name Brilinta among others, is a medication used for the prevention of stroke, heart attack and other events in people with acute coronary syndrome, meaning problems with blood supply in the coronary arteries. It acts as a platelet aggregation inhibitor by antagonising the P2Y12 receptor.The drug is produced by AstraZeneca.
It was approved for use in the European Union by the European Medicines Agency on 3 December 2010,and by the US Food and Drug Administration on 20 July 2011.
Ticagrelor is used for the prevention of thrombotic events (for example stroke or heart attack) in different categories of patients. The drug is combined with acetylsalicylic acid unless the latter is contraindicated.The PLATO trial has evidence to suggest that the use of ticagrelor as a pre-treatment in patients with non-ST elevation acute coronary syndrome (non-ST ACS) is superior than using clopidogrel in decreasing ischemic events and the total mortality independent of patients undergoing percutaneous coronary intervention.
The FDA indication for ticagrelor is reduction of the rate of cardiovascular death, myocardial infarction (MI), and stroke in people with acute coronary syndrome [ citation needed ]or history of myocardial infarction.
According to ESC 2017 guidelines, Dual Antiplatelet Therapy (DAPT) with Ticagrelor in combination with Acetylsalicylic acid (Aspirin) is the preferred treatment in patients with acute coronary syndrome with or without ST segment elevation, irrespective of the initial treatment strategy – invasive or non-invasive (IB level of evidence)however if there is a plan for PCI, administration of thrombolysis or the presence of some other patient factors (e.g. high bleeding risk) other antiplatelet agents are recommended. The 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy provides similar recommendations, although with a lower level of evidence (IIaB). Furthermore, the 2017 ESC Focused Update on Duration of Dual Antiplatelet Therapy allows physicians to administer ticagrelor to patients with stable coronary artery disease undergoing percutaneous coronary intervention after taking thrombotic and haemorrhagic risk into consideration.
Ticagrelor was not found to be superior to aspirin in reducing the rate of stroke, myocardial infarction or death in people with acute ischemic stroke or transient ischemic attack.When associated with ipsilateral atherosclerotic stenosis, however, ticagrelor was found to be superior to aspirin. Further studies are required to assess the role of ticagrelor in acute cerebrovascular disease.
A study compared ticagrelor and clopidogrel in patients with acute coronary syndrome (PLATO Trial) showed that patients treated with ticagrelor had a lower risk of infection-related deaths.The Targeting Platelet-Leukocyte Aggregates in Pneumonia With Ticagrelor (XANTHIPPE) study showed improvement in lung function in patients hospitalized for pneumonia in patients using ticagrelor.
Contraindications to ticagrelor are active bleeding, increased risk of bradycardia, concomitant therapy of ticagrelor and strong cytochrome P-450 3A (CYP3A4) inhibitors and moderate or severe hepatic impairment due to the risk of increased exposure to ticagrelor.
The common adverse effects are increased risk of bleeding (which may be severe)and shortness of breath (dyspnoea). Dyspnoea is usually mild to moderate in intensity, occurs in the first month of treatment, is often self-limiting, and the need for discontinuation is rare. It does not impact on efficacy or safety outcomes in people with acute coronary syndrome (ACS) and has no association with any adverse changes in heart and lung function.
Ventricular pauses ≥3 seconds may occur in ACS patients the first week of treatment, but are likely to be mostly asymptomatic and transient, without causing increased clinical bradycardic adverse events.Caution is recommended when using ticagrelor in patients with advanced sinoatrial node disease. Allergic skin reactions such as rash and itching have been observed in less than 1% of patients.
Inhibitors of the liver enzyme CYP3A4, such as ketoconazole and possibly grapefruit juice, increase blood plasma levels of ticagrelor and consequently can lead to bleeding and other adverse effects. Ticagrelor is a weak CYP3A4 inhibitorand is known to increase the concentrations of CYP3A4 metabolised medications, however this interaction is unlikely to be clinically significant for atorvastatin and simvastatin at recommended doses. CYP3A4 inducers, for example rifampicin and possibly St. John's wort, can reduce the effectiveness of ticagrelor. There is no evidence for interactions via CYP2C9.
The drug also inhibits P-glycoprotein (P-gp), leading to increased plasma levels of digoxin, ciclosporin and other P-gp substrates. Levels of ticagrelor and AR-C124910XX (the active metabolite of ticagrelor formed by O-deethylation) are not significantly influenced by P-gp inhibitors.
It is recommended to use low-dose aspirin (75–100 mg per day) with ticagrelor as dual antiplatelet therapy (DAPT). The combination of ticagrelor with aspirin doses greater than 100 mg per day may be less effective.
Like the thienopyridines prasugrel, clopidogrel and ticlopidine, ticagrelor blocks adenosine diphosphate (ADP) receptors of subtype P2Y12. In contrast to the other antiplatelet drugs, ticagrelor has a binding site different from ADP, making it an allosteric antagonist, and the blockage is reversible.Moreover, the drug does not need hepatic activation, which might work better for patients with genetic variants regarding the enzyme CYP2C19 (although it is not certain whether clopidogrel is significantly influenced by such variants).
Ticagrelor is absorbed quickly from the gut, the bioavailability being 36%, and reaches its peak concentration after about 1.5 hours. The main metabolite, AR-C124910XX, is formed quickly via CYP3A4 by de-hydroxyethylation at position 5 of the cyclopentane ring. mg (the sevenfold daily dose). The metabolite reaches 30–40% of ticagrelor's plasma concentrations. Drug and metabolite are mainly excreted via bile and feces.It peaks after about 2.5 hours. Both ticagrelor and AR-C124910XX are bound to plasma proteins (>99.7%), and both are pharmacologically active. Blood plasma concentrations are linearly dependent on the dose up to 1260
Plasma concentrations of ticagrelor are slightly increased (12–23%) in elderly patients, women, patients of Asian ethnicity, and patients with mild hepatic impairment. They are decreased in patients that self-identified as 'black' and those with severe renal impairment. These differences are not considered clinically relevant. In Japanese people, concentrations are 40% higher than in Caucasians, or 20% after body weight correction. The drug has not been tested in patients with severe hepatic impairment.
Consistently with its reversible mode of action, ticagrelor is known to act faster and shorter than clopidogrel.This means it has to be taken twice instead of once a day which is a disadvantage in respect of compliance, but its effects are more quickly reversible which can be useful before surgery or if side effects occur.
Ticagrelor is a nucleoside analogue: the cyclopentane ring is similar to the sugar ribose, and the nitrogen rich aromatic ring system resembles the nucleobase purine, giving the molecule an overall similarity to adenosine. The substance has low solubility and low permeability under the Biopharmaceutics Classification System.
The PLATO trialfound that ticagrelor had better mortality rates than clopidogrel (9.8% vs. 11.7%, p<0.001) in treating patients with acute coronary syndrome. Patients given ticagrelor were less likely to die from vascular causes, heart attack, or stroke but had greater chances of non-lethal bleeding (16.1% vs. 14.6%, p=0.0084) and higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, p=0.03). While the patient group on ticagrelor had more instances of fatal intracranial bleeding, there were significantly fewer cases of fatal non-intracranial bleeding, leading to an overall neutral effect on fatal or life-threatening bleeding vs. clopidogrel (p=0.70). Rates of major bleeding were not different. Discontinuation of the study drug due to adverse events occurred more frequently with ticagrelor than with clopidogrel (in 7.4% of patients vs. 6.0%, p<0.001).
The PLATO trial showed a statistically insignificant trend toward worse outcomes with ticagrelor versus clopidogrel among US patients in the study – who comprised 1800 of the total 18,624 patients. The hazard ratio actually reversed for the composite end point cardiovascular (death, MI, or stroke): 12.6% for patients given ticagrelor and 10.1% for patients given clopidogrel (HR = 1.27). Some believe the results could be due to differences in aspirin maintenance doses, which are higher in the United States.Others state that the central adjudicating committees found an extra 45 MIs in the clopidogrel (comparator) arm but none in the ticagrelor arm, which improved the MI outcomes with ticagrelor. Without this adjudication the trials' primary efficacy outcomes should not be significant.
Also, there are some disagreement regarding efficacy and safety of ticagrelor in Asian patients. As mentioned before, ticagrelor provides significant thrombotic benefits, but increases bleeding risk at the same time.It's especially of crucial importance for Asian individuals, as they are well-known to be prone to bleeding events. Current evidence on the risk/benefit ratio of ticagrelor in this vulnerable population is somewhat controversial. Some meta-analyses of randomized controlled trials (RCTs) suggested that ticagrelor was associated with an increase in serious haemorrhagic events, which wasn't accompanied with ischaemic advantages in Asian patients. However, these meta-analyses were mainly based on results of two RCTs with relatively small sample size and other pitfalls in design, which prevents researchers from generalization on the whole Asian population. On the other hand, recent meta-analysis of observational studies implied that ticagrelor provides ischaemic benefits (mainly by reducing the risk of stroke) without a significant increase in major bleeding. The "real-world" settings gave strong support for this study, nevertheless, further high-quality research are of vital importance to provide definite recommendations for clinical practice.
In 2019, the results of the ISAR-REACT 5 trial was published, comparing ticagrelor and prasugrel in patients with acute coronary syndrome.
A study published in JAMA Cardiology showed antibacterial activity in conventional antiplatelet doses against antibiotic-resistant Gram-positive bacteria, warranting further randomized trials to evaluate its value as antibiotic.
Aspirin, also known as acetylsalicylic acid (ASA), is a medication used to reduce pain, fever, or inflammation. Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease, pericarditis, and rheumatic fever. Aspirin given shortly after a heart attack decreases the risk of death. Aspirin is also used long-term to help prevent further heart attacks, ischaemic strokes, and blood clots in people at high risk. It may also decrease the risk of certain types of cancer, particularly colorectal cancer. For pain or fever, effects typically begin within 30 minutes. Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) and works similarly to other NSAIDs but also suppresses the normal functioning of platelets.
Coronary artery disease (CAD), also known as coronary heart disease (CHD), ischemic heart disease (IHD), or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of plaque (atherosclerosis) in the arteries of the heart. It is the most common of the cardiovascular diseases. Types include stable angina, unstable angina, myocardial infarction, and sudden cardiac death. A common symptom is chest pain or discomfort which may travel into the shoulder, arm, back, neck, or jaw. Occasionally it may feel like heartburn. Usually symptoms occur with exercise or emotional stress, last less than a few minutes, and improve with rest. Shortness of breath may also occur and sometimes no symptoms are present. In many cases, the first sign is a heart attack. Other complications include heart failure or an abnormal heartbeat.
Angioplasty, also known as balloon angioplasty and percutaneous transluminal angioplasty (PTA), is a minimally invasive endovascular procedure used to widen narrowed or obstructed arteries or veins, typically to treat arterial atherosclerosis. A deflated balloon attached to a catheter is passed over a guide-wire into the narrowed vessel and then inflated to a fixed size. The balloon forces expansion of the blood vessel and the surrounding muscular wall, allowing an improved blood flow. A stent may be inserted at the time of ballooning to ensure the vessel remains open, and the balloon is then deflated and withdrawn. Angioplasty has come to include all manner of vascular interventions that are typically performed percutaneously.
An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation, where anticoagulants have little effect.
Clopidogrel, sold under the trade name Plavix among others, is an antiplatelet medication used to reduce the risk of heart disease and stroke in those at high risk. It is also used together with aspirin in heart attacks and following the placement of a coronary artery stent. It is taken by mouth. Onset of effects is about two hours and lasts for five days.
Ticlopidine is an antiplatelet drug in the thienopyridine family which is an adenosine diphosphate (ADP) receptor inhibitor. Research initially showed that it was useful for preventing strokes and coronary stent occlusions. However, because of its rare but serious side effects of neutropenia and thrombotic thrombocytopenic purpura it was primarily used in patients in whom aspirin was not tolerated, or in whom dual antiplatelet therapy was desirable. With the advent of newer and safer antiplatelet drugs such as clopidogrel and ticagrelor, its use remained limited.
Prasugrel, sold under the brand name Effient in the US, Australia and India, and Efient in the EU) is a medication used to prevent formation of blood clots. It is a platelet inhibitor and an irreversible antagonist of P2Y12 ADP receptors and is of the thienopyridine drug class. It was developed by Daiichi Sankyo Co. and produced by Ube and marketed in the United States in cooperation with Eli Lilly and Company.
Acute coronary syndrome (ACS) is a syndrome due to decreased blood flow in the coronary arteries such that part of the heart muscle is unable to function properly or dies. The most common symptom is chest pain, often radiating to the left shoulder or angle of the jaw, crushing, central and associated with nausea and sweating. Many people with acute coronary syndromes present with symptoms other than chest pain, particularly women, older patients, and patients with diabetes mellitus.
Unstable angina (UA), also called crescendo angina, is a type of angina pectoris that is irregular. It is also classified as a type of acute coronary syndrome (ACS).
Percutaneous coronary intervention (PCI) is a surgical procedure used to treat narrowing of the coronary arteries of the heart found in coronary artery disease. The process involves combining coronary angioplasty with stenting, which is the insertion of a permanent wire-meshed tube that is either drug eluting (DES) or composed of bare metal (BMS). The stent delivery balloon from the angioplasty catheter is inflated with media to force contact between the struts of the stent and the vessel wall, thus widening the blood vessel diameter. After accessing the blood stream through the femoral or radial artery, the procedure uses coronary catheterization to visualise the blood vessels on X-ray imaging. After this, an interventional cardiologist can perform a coronary angioplasty, using a balloon catheter in which a deflated balloon is advanced into the obstructed artery and inflated to relieve the narrowing; certain devices such as stents can be deployed to keep the blood vessel open. Various other procedures can also be performed.
P2Y12 is a chemoreceptor for adenosine diphosphate (ADP) that belongs to the Gi class of a group of G protein-coupled (GPCR) purinergic receptors. This P2Y receptor family has several receptor subtypes with different pharmacological selectivity, which overlaps in some cases, for various adenosine and uridine nucleotides. The P2Y12 receptor is involved in platelet aggregation and is thus a biological target for the treatment of thromboembolisms and other clotting disorders. Two transcript variants encoding the same isoform have been identified for this gene.
Bivalirudin (Bivalitroban), sold under the brand names Angiomax and Angiox and manufactured by The Medicines Company, is a direct thrombin inhibitor (DTI).
The Thrombolysis In Myocardial Infarction, or TIMI Study Group, is an Academic Research Organization (ARO) affiliated with Brigham and Women's Hospital and Harvard Medical School dedicated to advancing the knowledge and care of patients suffering from cardiovascular disease. The TIMI Study Group provides robust expertise in the key aspects of a clinical trial, including academic leadership, global trial management, biostatistics, clinical event adjudication, safety desk, medical hotline, and core laboratories. The group has its headquarters in Boston, Massachusetts.
Vorapaxar is a thrombin receptor antagonist based on the natural product himbacine, discovered by Schering-Plough and developed by Merck & Co.
Thienopyridines are a class of selective, irreversible ADP receptor/P2Y12 inhibitors used for their anti-platelet activity.
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to a part of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may travel into the shoulder, arm, back, neck or jaw. Often it occurs in the center or left side of the chest and lasts for more than a few minutes. The discomfort may occasionally feel like heartburn. Other symptoms may include shortness of breath, nausea, feeling faint, a cold sweat or feeling tired. About 30% of people have atypical symptoms. Women more often present without chest pain and instead have neck pain, arm pain or feel tired. Among those over 75 years old, about 5% have had an MI with little or no history of symptoms. An MI may cause heart failure, an irregular heartbeat, cardiogenic shock or cardiac arrest.
Cangrelor, sold under the brand name Kengreal in the United States and Kengrexal in the European Union) is a P2Y12 inhibitor FDA approved as of June 2015 as an antiplatelet drug for intravenous application. Some P2Y12 inhibitors are used clinically as effective inhibitors of adenosine diphosphate-mediated platelet activation and aggregation. Unlike clopidogrel (Plavix), which is a prodrug, cangrelor is an active drug not requiring metabolic conversion.
Adenosine diphosphate (ADP) receptor inhibitors are a drug class of antiplatelet agents, used in the treatment of acute coronary syndrome (ACS) or in preventive treatment for patients who are in risk of thromboembolism, myocardial infarction or a stroke. These drugs antagonize the P2Y12 platelet receptors and therefore prevent the binding of ADP to the P2Y12 receptor. This leads to a decrease in aggregation of platelets, prohibiting thrombus formation. The P2Y12 receptor is a surface bound protein found on blood platelets. They belong to G protein-coupled purinergic receptors (GPCR) and are chemoreceptors for ADP.
Management of acute coronary syndrome is targeted against the effects of reduced blood flow to the afflicted area of the heart muscle, usually because of a blood clot in one of the coronary arteries, the vessels that supply oxygenated blood to the myocardium. This is achieved with urgent hospitalization and medical therapy, including drugs that relieve chest pain and reduce the size of the infarct, and drugs that inhibit clot formation; for a subset of patients invasive measures are also employed. Basic principles of management are the same for all types of acute coronary syndrome. However, some important aspects of treatment depend on the presence or absence of elevation of the ST segment on the electrocardiogram, which classifies cases upon presentation to either ST segment elevation myocardial infarction (STEMI) or non-ST elevation acute coronary syndrome (NST-ACS); the latter includes unstable angina and non-ST elevation myocardial infarction (NSTEMI). Treatment is generally more aggressive for STEMI patients, and reperfusion therapy is more often reserved for them. Long-term therapy is necessary for prevention of recurrent events and complications.
Regrelor is an experimental antiplatelet drug that was under investigation by Merck Sharp and Dohme in human clinical trials. Although it was initially found to be well tolerated in healthy subjects, safety concerns led to cessation of clinical trials.