A Comprehensive Monograph on Ticagrelor: Pharmacology, Clinical Evidence, and Therapeutic Use

Section 1: Introduction and Overview

1.1 Executive Summary

Ticagrelor is a potent, orally administered antiplatelet agent belonging to the cyclo-pentyl-triazolo-pyrimidine (CPTP) chemical class.[1] It represents a significant development in the management of atherothrombotic disease, functioning as a first-in-class, direct-acting, and reversibly binding antagonist of the P2Y12 adenosine diphosphate (ADP) receptor on platelets.[2] This pharmacological profile distinguishes it fundamentally from the thienopyridine class of P2Y12 inhibitors, such as clopidogrel and prasugrel. A key differentiator is that Ticagrelor is not a prodrug and therefore does not require hepatic metabolic activation to exert its therapeutic effect, leading to a more rapid and consistent onset of platelet inhibition.[2]

The primary clinical utility of Ticagrelor is the prevention of thrombotic cardiovascular events. It is indicated for patients with Acute Coronary Syndrome (ACS)—encompassing ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina—or those with a history of Myocardial Infarction (MI).[4] Its approval for this core indication was based on the landmark PLATelet inhibition and patient Outcomes (PLATO) trial, which demonstrated the superiority of Ticagrelor over clopidogrel in reducing the composite endpoint of cardiovascular death, MI, or stroke in the ACS setting.[8]

Subsequent clinical development has expanded its approved uses to include long-term secondary prevention in patients with a history of MI, primary prevention of a first MI or stroke in high-risk patients with Coronary Artery Disease (CAD), and secondary prevention of stroke in patients with an acute ischemic stroke or high-risk Transient Ischemic Attack (TIA).[7] Marketed under brand names including Brilinta in the United States and Brilique in the European Union, Ticagrelor has become a cornerstone of dual antiplatelet therapy (DAPT) in multiple clinical guidelines.[1]

1.2 Scope of the Report

This monograph provides a definitive, evidence-based review of Ticagrelor. It aims to synthesize a comprehensive body of knowledge, ranging from the drug's fundamental chemical and physicochemical properties to its complex molecular mechanisms of action, pharmacokinetic profile, and extensive clinical trial evidence. The report will critically analyze its therapeutic applications across various indications, delineate its safety profile, including major warnings and adverse events, and detail its clinically significant drug and food interactions. Finally, it will cover dosing, administration, and the drug's regulatory history to provide a complete picture for clinicians, pharmacologists, and researchers. The analysis is built upon a thorough review of scientific literature, clinical trial data, and regulatory documents.

Section 2: Chemical Identity and Physicochemical Properties

2.1 Nomenclature and Identifiers

A comprehensive identification of a pharmaceutical agent requires a systematic cataloging of its various names and registry codes used throughout its development and clinical use. For Ticagrelor, these identifiers are as follows:

• Generic Name: Ticagrelor [4]
• Brand Names: Brilinta (United States), Brilique (European Union), Possia (European Union) [4]
• Developmental Codes: AZD6140, AZD 6140, AZD-6140, AR-C 126532XX [4]
• Systematic (IUPAC) Name: (1S,2S,3R,5S)-3-amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol [5]
• Key Registry Numbers:
• CAS Number: 274693-27-5 [14]
• DrugBank ID: DB08816 [4]
• PubChem CID: 9871419 [5]
• European Community (EC) Number: 619-540-9 [5]
• ChEBI ID: CHEBI:68558 [5]
• ChEMBL ID: CHEMBL398435 [5]

2.2 Chemical Structure and Class

Ticagrelor is a member of the cyclo-pentyl-triazolo-pyrimidine (CPTP) chemical class.[1] Structurally, it is designed as an adenosine isostere. This design is not arbitrary; the molecule's cyclopentane ring serves as a structural mimic of the ribose sugar in adenosine, while the nitrogen-rich triazolo[4,5-d]pyrimidine moiety functions as an analog of the nucleobase adenine.[5] This structural mimicry of adenosine is a critical feature that provides a basis for understanding not only its primary target engagement but also its secondary pharmacological effects.

• Molecular Formula: C23​H28​F2​N6​O4​S [5]
• Molecular Weight: The average molecular weight is consistently reported as approximately 522.6 g/mol.[14] More precise values are 522.568 g/mol [4] and 522.57 g/mol.[20]
• Structural Identifiers:
• SMILES: CCCSC1=NC(=C2C(=N1)N(N=N2)[C@@H]3CC@@HOCCO)N[C@@H]4C[C@H]4C5=CC(=C(C=C5)F)F
• InChIKey: OEKWJQXRCDYSHL-FNOIDJSQSA-N

2.3 Physicochemical Properties

The physical and chemical properties of Ticagrelor dictate its formulation, stability, and pharmacokinetic behavior. It is described as a crystalline solid or powder with a melting point of 140-142°C. Four distinct polymorphs have been identified, with a single, stable form selected for all preclinical and clinical development, which notably does not convert to other forms upon storage.

A critical characteristic of Ticagrelor is its classification as a Biopharmaceutics Classification System (BCS) Class 4 compound, defined by both low aqueous solubility and low membrane permeability. This property presents significant challenges for oral drug delivery, as it can lead to poor and variable absorption. The formulation of the final drug product, BRILINTA tablets, directly addresses this challenge. The tablets are an immediate-release, film-coated dosage form containing excipients such as mannitol (a filler), dibasic calcium phosphate (a filler/binder), sodium starch glycolate (a superdisintegrant to promote rapid tablet breakup), and hydroxypropyl cellulose (a binder and potential solubilizer). This formulation is engineered to overcome the inherent physicochemical limitations of the active ingredient and facilitate adequate dissolution and absorption upon oral administration.

Regarding solubility in organic solvents, Ticagrelor is soluble in dimethylformamide (DMF) at 25 mg/mL, dimethyl sulfoxide (DMSO) at 20 mg/mL, and ethanol at 15 mg/mL. For storage, research-grade material is typically kept at -20°C, and the compound has demonstrated stability for at least four years under appropriate conditions.

Table 2.1: Comprehensive Identification and Physicochemical Properties of Ticagrelor

Property	Value	Source(s)
Generic Name	Ticagrelor
IUPAC Name	(1S,2S,3R,5S)-3-amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol
CAS Number	274693-27-5
Molecular Formula	C23​H28​F2​N6​O4​S
Molecular Weight	522.57 g/mol
Physical Form	Crystalline solid; powder
Melting Point	140-142°C
BCS Class	Class 4 (Low Solubility, Low Permeability)
Key Solubilities	DMF: 25 mg/mL; DMSO: 20 mg/mL; Ethanol: 15 mg/mL
SMILES	CCCSC1=NC(=C2C(=N1)N(N=N2)[C@@H]3COCCO)N[C@@H]4C[C@H]4C5=CC(=C(C=C5)F)F
InChIKey	OEKWJQXRCDYSHL-FNOIDJSQSA-N

Section 3: Pharmacology and Molecular Mechanism of Action

3.1 Primary Mechanism: P2Y12 Receptor Antagonism

Ticagrelor is classified as an antiplatelet medication, specifically a P2Y12 platelet inhibitor. Its primary mechanism of action is the selective and reversible antagonism of the platelet purinergic P2Y12 receptor, which plays a central role in amplifying platelet activation and aggregation.

The P2Y12 receptor is a G-protein coupled receptor (GPCR) that, upon binding its endogenous ligand ADP, couples to an inhibitory G-protein, Gαi. This activation leads to the inhibition of the enzyme adenylyl cyclase, resulting in a decrease in intracellular levels of cyclic adenosine monophosphate (cAMP). Lower cAMP levels reduce the activity of protein kinase A (PKA), which in turn decreases the phosphorylation of key substrates like vasodilator-stimulated phosphoprotein (VASP), ultimately promoting platelet activation, shape change, and aggregation.

Ticagrelor disrupts this signaling cascade through a unique mode of inhibition. It binds reversibly to the P2Y12 receptor at an allosteric site, meaning a location distinct from where ADP binds. This interaction induces a conformational change in the receptor that "locks" it in an inactive state, thereby preventing ADP from binding and initiating the downstream signaling pathway. Because it does not compete directly with ADP for the same binding site, it is classified as a non-competitive antagonist. This reversible, non-competitive antagonism effectively blocks ADP-mediated platelet aggregation and is the principal mechanism by which Ticagrelor exerts its antithrombotic effect.

3.2 Secondary and Novel Mechanisms

Beyond its primary action at the P2Y12 receptor, Ticagrelor possesses additional pharmacological properties that contribute to its overall effect and distinguish it from other agents. These secondary mechanisms may help explain both its enhanced clinical efficacy and its unique side-effect profile.

3.2.1 Inhibition of Equilibrative Nucleoside Transporter 1 (ENT1)

Ticagrelor is a potent inhibitor of the equilibrative nucleoside transporter 1 (ENT1), with a reported Ki value of 41 nM. ENT1 is the primary transporter responsible for the cellular reuptake of adenosine from the extracellular space into cells like erythrocytes. By blocking ENT1, Ticagrelor effectively increases the local extracellular concentration of adenosine near the platelet surface and in the wider circulation. This elevated adenosine can then stimulate platelet A2A receptors, which are Gs-coupled GPCRs. Activation of A2A receptors stimulates adenylyl cyclase, increases cAMP levels, and thus provides an additional, independent pathway for platelet inhibition. This dual mechanism—direct P2Y12 blockade and indirect adenosine-mediated inhibition—represents a novel approach to antiplatelet therapy. The systemic effects of increased adenosine, such as vasodilation and modulation of inflammation, have been hypothesized to contribute to the unexpected mortality benefit observed with Ticagrelor in the PLATO trial, an effect not seen with other P2Y12 inhibitors. This same mechanism is the leading explanation for the common side effect of dyspnea, as adenosine is a known mediator of shortness of breath.

3.2.2 Inverse Agonism

In vitro studies have demonstrated that Ticagrelor also functions as an inverse agonist at the P2Y12 receptor. A neutral antagonist simply blocks an agonist from binding, whereas an inverse agonist actively reduces the receptor's basal or constitutive signaling activity, which can occur even in the absence of an agonist. This property means Ticagrelor can downregulate P2Y12 receptor signaling below its baseline level, an effect not observed with the active metabolites of thienopyridines like prasugrel. In highly prothrombotic states such as ACS, where platelets may be "primed" and exhibit heightened basal activity, this inverse agonism could provide a theoretical advantage over agents that only block agonist-induced activation.

3.3 Comparison with Thienopyridines (Clopidogrel/Prasugrel)

The development of Ticagrelor was a direct response to the known limitations of the thienopyridine class of P2Y12 inhibitors. The key differences are clinically significant:

• Metabolic Activation: Ticagrelor is an orally active parent drug that does not require metabolic activation. In stark contrast, clopidogrel and prasugrel are prodrugs that are inactive until they undergo a multi-step conversion in the liver by cytochrome P450 enzymes to form their active metabolites. This distinction is critical. Ticagrelor's direct action leads to a much faster onset of platelet inhibition, achieving significant effects within 30 minutes of a loading dose, which is faster than can be achieved with clopidogrel. Furthermore, it bypasses the genetic variability in CYP2C19 enzymes that leads to "clopidogrel non-responders" and inconsistent platelet inhibition.
• Reversibility of Binding: Ticagrelor binds reversibly to the P2Y12 receptor, with its antiplatelet effect diminishing as plasma concentrations fall. Thienopyridines bind irreversibly, permanently disabling the receptor for the entire lifespan of the platelet (7-10 days). This reversibility gives Ticagrelor a faster offset of action, allowing for a more rapid restoration of platelet function when the drug is discontinued. This is a significant advantage in managing bleeding events or when a patient requires urgent surgery.
• Potency and Consistency: Clinical studies have consistently shown that Ticagrelor produces a higher and more predictable level of inhibition of platelet aggregation (IPA) throughout the dosing interval compared to standard doses of clopidogrel.

Section 4: Pharmacokinetics and Metabolism (ADME)

The pharmacokinetic profile of Ticagrelor, including its absorption, distribution, metabolism, and excretion (ADME), is characterized by rapid absorption, extensive metabolism by CYP3A4 into an equipotent active metabolite, and elimination primarily via the feces.

4.1 Absorption

Following oral administration, Ticagrelor is absorbed rapidly, with the time to reach maximum plasma concentration (Tmax) occurring at a median of 1.5 hours. The absolute oral bioavailability is modest, estimated at 36%, a consequence of its BCS Class 4 properties (low solubility and permeability). A single 200 mg oral dose in healthy subjects resulted in a peak plasma concentration (Cmax) of 923 ng/mL and a total exposure (AUC) of 6675 ng*h/mL. The drug can be taken with or without food, as food does not significantly impact its absorption. However, a significant food interaction exists with grapefruit juice, which should be avoided during therapy.

4.2 Distribution

Ticagrelor has a moderate steady-state volume of distribution (Vd) of 88 L, suggesting distribution into tissues beyond the plasma volume. Both the parent drug and its primary active metabolite are highly bound to plasma proteins (>99%), particularly albumin. Studies using radiolabelled Ticagrelor found that radioactivity was largely confined to the plasma compartment rather than partitioning into red blood cells, further supporting its high protein binding.

4.3 Metabolism

Ticagrelor undergoes extensive hepatic metabolism, which is the cornerstone of its clearance and the primary determinant of its drug-drug interaction profile.

• Primary Pathway and Active Metabolite: The metabolism is predominantly mediated by the cytochrome P450 enzyme CYP3A4, with a minor contribution from CYP3A5. The main metabolic transformation is the O-deethylation of Ticagrelor to form its major active metabolite, AR-C124910XX. This metabolite is not merely a byproduct; it is pharmacologically active and has been shown to be approximately equipotent to the parent drug in its P2Y12 receptor antagonism. The systemic exposure (AUC) to AR-C124910XX is substantial, representing about 30-40% of the exposure to the parent compound, and it therefore contributes significantly to the overall therapeutic effect.
• Other Pathways: A secondary, minor metabolic pathway involves N-dealkylation of Ticagrelor to form an inactive metabolite, AR-C133913XX. Both the parent drug and its metabolites can undergo subsequent Phase II metabolism, specifically glucuronidation, prior to excretion.
• Pharmacogenomics: The heavy reliance on CYP3A enzymes raises questions about genetic polymorphisms. Studies in a Chinese population found that the CYP3A4*1G polymorphism led to significantly higher plasma concentrations of the active metabolite AR-C124910XX. However, this pharmacokinetic difference did not translate into a clinically detectable change in the pharmacodynamic response (i.e., platelet inhibition). Consequently, dose adjustments based on CYP3A4 or CYP3A5 genotypes are not currently recommended. Critically, and in contrast to clopidogrel, the efficacy of Ticagrelor is not influenced by the genetic status of CYP2C19.

4.4 Excretion

The elimination of Ticagrelor and its metabolites occurs primarily through hepatobiliary excretion into the feces. Following administration of a single oral radiolabelled dose, a mean of 57.8% of the radioactivity was recovered in the feces, while 26.5% was recovered in the urine over 168 hours. Renal clearance is a minor route of elimination for the parent drug and its active metabolite; less than 1% of the administered dose is excreted unchanged in the urine. The active metabolite, AR-C124910XX, was a major component found in the feces (accounting for 21.7% of recovered drug-related material), underscoring the importance of biliary excretion.

The plasma half-life (t1/2​) of Ticagrelor is approximately 8 hours, while its active metabolite, AR-C124910XX, has a longer half-life of about 12 hours. This pharmacokinetic profile, particularly the moderate half-lives of both the parent and active metabolite, supports the twice-daily dosing regimen required to maintain consistent platelet inhibition.

Table 4.1: Key Pharmacokinetic Parameters of Ticagrelor and its Active Metabolite (AR-C124910XX)

Parameter	Ticagrelor (Parent Drug)	AR-C124910XX (Active Metabolite)	Source(s)
Tmax (median)	1.5 hours	3.0 hours
Oral Bioavailability	~36%	N/A (Formed from parent)
Volume of Distribution (Vd)	88 L	Not specified
Plasma Protein Binding	>99%	>99%
Plasma Half-life (t1/2​)	~8 hours	~12 hours
Primary Metabolizing Enzyme	CYP3A4, CYP3A5	N/A
Primary Route of Elimination	Hepatic metabolism / Fecal excretion	Fecal excretion

Section 5: Clinical Evidence and Therapeutic Applications

The clinical utility of Ticagrelor has been established through a series of large, randomized controlled trials, leading to its approval for several distinct indications related to the prevention of atherothrombotic events.

5.1 Approved Indications

The U.S. Food and Drug Administration (FDA) has approved Ticagrelor for the following patient populations and conditions :

1. Acute Coronary Syndrome (ACS) or a History of Myocardial Infarction (MI): To reduce the rate of a composite endpoint of cardiovascular (CV) death, MI, and stroke. In patients with ACS who have been treated with a coronary stent, Ticagrelor also reduces the risk of stent thrombosis.
2. High-Risk Coronary Artery Disease (CAD): To reduce the risk of a first MI or stroke in patients with CAD who are at high risk for such events but have no prior history of MI or stroke. The efficacy for this indication was established in a population that included patients with type 2 diabetes.
3. Acute Ischemic Stroke or High-Risk Transient Ischemic Attack (TIA): To reduce the risk of a subsequent stroke in patients presenting with an acute ischemic stroke (NIH Stroke Scale score ≤5) or a high-risk TIA.

5.2 Pivotal Clinical Trial Analysis: ACS (The PLATO Trial)

The cornerstone of Ticagrelor's approval for ACS was the PLATO (PLATelet inhibition and patient Outcomes) trial. This large-scale, randomized, double-blind study enrolled 18,624 patients hospitalized with ACS (with or without ST-segment elevation) and compared a strategy of Ticagrelor (180 mg loading dose, then 90 mg twice daily) plus aspirin against the then-standard-of-care, clopidogrel (300-600 mg loading dose, then 75 mg once daily) plus aspirin.

• Efficacy Outcomes: At 12 months, Ticagrelor demonstrated clear superiority. The primary efficacy endpoint—a composite of CV death, MI, or stroke—occurred in 9.8% of patients in the Ticagrelor group versus 11.7% in the clopidogrel group (Hazard Ratio 0.84, 95% Confidence Interval [CI] 0.77–0.92; p<0.001). This benefit was consistent and driven by statistically significant reductions in the individual components of CV death (4.0% vs. 5.1%; HR 0.79) and MI (5.8% vs. 6.9%; HR 0.84). Notably, Ticagrelor also led to a significant reduction in all-cause mortality (4.5% vs. 5.9%; HR 0.78) and a lower rate of definite or probable stent thrombosis (2.2% vs. 2.9%).
• Safety Outcomes: The primary safety endpoint of overall major bleeding did not differ significantly between the two groups (11.6% for Ticagrelor vs. 11.2% for clopidogrel; p=0.43). However, Ticagrelor was associated with a higher rate of non-coronary artery bypass graft (CABG)-related major bleeding (4.5% vs. 3.8%; p=0.03). There was no difference in fatal bleeding or CABG-related major bleeding.

5.3 Long-Term Secondary Prevention (The PEGASUS-TIMI 54 Trial)

To evaluate its role beyond the first year after an event, the PEGASUS-TIMI 54 trial was conducted. This study randomized over 21,000 patients who had a prior MI (1 to 3 years earlier) to receive either Ticagrelor (at a 90 mg twice-daily dose or a 60 mg twice-daily dose) or placebo, with all patients continuing on low-dose aspirin. Both doses of Ticagrelor were found to be superior to placebo in reducing the primary composite endpoint of CV death, MI, or stroke. This trial provided the pivotal evidence for the FDA's expanded approval of Ticagrelor for long-term secondary prevention, establishing the 60 mg twice-daily dose for this indication.

5.4 Acute Ischemic Stroke/TIA (The THALES and SOCRATES Trials)

Ticagrelor's role in stroke prevention was investigated in two major trials with differing designs and outcomes.

• The SOCRATES trial compared Ticagrelor monotherapy against aspirin monotherapy in patients with acute ischemic stroke or high-risk TIA. The trial did not meet its primary endpoint, as Ticagrelor was not statistically superior to aspirin in reducing the composite of stroke, MI, or death (6.7% vs. 7.5%; HR 0.89; p=0.07).
• The THALES trial evaluated a dual antiplatelet strategy, comparing Ticagrelor plus aspirin to aspirin alone in the same patient population. The combination of Ticagrelor and aspirin was superior to aspirin alone in reducing the primary endpoint of stroke or death at 30 days (5.5% vs. 6.6%; HR 0.83; p=0.02). This benefit, however, came at the cost of a significantly increased risk of severe bleeding (0.5% vs. 0.1%; HR 3.99; p=0.001). The positive results from THALES led to the FDA approval for this specific indication.

5.5 Investigational Use: Peripheral Artery Disease (The EUCLID Trial)

The potential benefit of Ticagrelor was explored in patients with stable, symptomatic peripheral artery disease (PAD) in the EUCLID trial. This large study (N=13,885) compared Ticagrelor monotherapy (90 mg twice daily) with clopidogrel monotherapy (75 mg once daily). The results were definitive but negative: the trial

failed to meet its primary endpoint. Ticagrelor was not found to be superior to clopidogrel in preventing the composite of CV death, MI, or ischemic stroke (11.4% vs. 11.3%; HR 1.01; p=0.90). Furthermore, more patients discontinued Ticagrelor due to adverse events, including dyspnea and bleeding.

The contrasting outcomes of PLATO and EUCLID are highly instructive. They underscore that the pathophysiology of acute coronary thrombosis is distinct from that of chronic, stable PAD. The potent, multi-faceted platelet inhibition provided by Ticagrelor appears to offer a significant advantage in the "hot," highly prothrombotic setting of an acute plaque rupture (ACS). In the more stable setting of chronic PAD, the more modest inhibition from clopidogrel appears sufficient, and the increased side-effect burden of a more potent agent negates any potential for incremental benefit. This highlights the critical principle that antiplatelet strategies must be tailored to the specific vascular bed and clinical acuity, and that benefits observed in one disease state cannot be automatically extrapolated to another.

Table 5.1: Summary of Pivotal Clinical Trials for Ticagrelor

Trial Acronym	Indication	N	Intervention	Comparator	Follow-up	Primary Efficacy Outcome (HR [95% CI]; p-value)	Source(s)
PLATO	Acute Coronary Syndrome (ACS)	18,624	Ticagrelor + Aspirin	Clopidogrel + Aspirin	12 months	CV Death, MI, or Stroke: 0.84 [0.77–0.92]; p<0.001
PEGASUS-TIMI 54	History of MI (1-3 yrs prior)	21,162	Ticagrelor (60/90mg) + Aspirin	Placebo + Aspirin	~33 months	CV Death, MI, or Stroke: Significant reduction vs placebo
THALES	Acute Ischemic Stroke / TIA	11,016	Ticagrelor + Aspirin	Aspirin Alone	30 days	Stroke or Death: 0.83 [0.71–0.96]; p=0.02
SOCRATES	Acute Ischemic Stroke / TIA	13,199	Ticagrelor Monotherapy	Aspirin Monotherapy	90 days	MI, Stroke, or Death: 0.89 [0.78–1.01]; p=0.07
EUCLID	Peripheral Artery Disease (PAD)	13,885	Ticagrelor Monotherapy	Clopidogrel Monotherapy	~30 months	CV Death, MI, or Ischemic Stroke: 1.01 [0.88–1.15]; p=0.90

Section 6: Safety Profile, Tolerability, and Risk Management

The safety profile of Ticagrelor is dominated by its primary pharmacological effect: the inhibition of platelet aggregation. This leads to an increased risk of bleeding, which is the most significant safety concern and is reflected in the drug's prominent FDA boxed warning.

6.1 FDA Boxed Warning

Ticagrelor's prescribing information includes a boxed warning that highlights several critical safety issues :

1. Bleeding Risk: It explicitly states that Ticagrelor, like other antiplatelet agents, can cause significant and sometimes fatal bleeding. The drug is contraindicated in patients with active pathological bleeding (such as a peptic ulcer or intracranial bleeding) and in those with a history of intracranial hemorrhage (ICH) due to the high risk of recurrence. It should also not be initiated in patients scheduled for urgent coronary artery bypass graft (CABG) surgery.
2. Discontinuation Risk: The warning emphasizes that stopping Ticagrelor prematurely increases the risk of subsequent cardiovascular events, including MI, stroke, and stent thrombosis. If discontinuation is necessary, it should be done under the guidance of a physician, and therapy should be resumed as soon as possible.
3. Aspirin Dose: The warning advises that maintenance doses of aspirin above 100 mg per day should be avoided when co-administered with Ticagrelor for ACS, as higher doses were observed to reduce the effectiveness of Ticagrelor in a subgroup of the PLATO trial.

6.2 Critical Analysis of the Aspirin Dose Warning

The warning regarding aspirin doses above 100 mg is one of the most debated aspects of Ticagrelor's label. This recommendation stemmed from a pre-specified but post-hoc subgroup analysis of the PLATO trial, which found that the benefit of Ticagrelor over clopidogrel was attenuated or lost in the North American cohort, where higher maintenance doses of aspirin were more common.

However, multiple analyses have challenged the biological and statistical validity of this finding. Critics point out that the observation was derived from a small subgroup, lacks a clear biological mechanism, and was not significant after multivariate adjustments for other baseline differences. The FDA's own internal review documents indicated that even aspirin doses above 300 mg did not show a statistically significant interaction for major vascular outcomes. While clinicians must adhere to the labeled warning and use aspirin doses of 75-100 mg, it is important to recognize that the scientific basis for a true pharmacological interaction remains controversial and may represent a statistical anomaly rather than a causal relationship.

6.3 Common and Serious Adverse Events

Beyond the general risk of bleeding, Ticagrelor is associated with several other notable adverse events:

• Bleeding: This is the most frequently reported adverse event, ranging from minor events like bruising and nosebleeds (epistaxis) to severe, life-threatening events like gastrointestinal hemorrhage or ICH. In the PLATO trial, while the rate of overall major bleeding was similar to clopidogrel, the rate of non-CABG-related major bleeding was significantly higher with Ticagrelor.
• Dyspnea (Shortness of Breath): This is a uniquely common side effect of Ticagrelor, reported in up to 21% of patients in clinical trials. The sensation is typically described as mild to moderate in intensity and is often transient or self-limiting, resolving with continued treatment. However, it can be distressing for patients and leads to drug discontinuation in a small percentage of cases. The mechanism is believed to be related to the increased local concentrations of adenosine resulting from Ticagrelor's inhibition of the ENT1 transporter.
• Bradyarrhythmias: Holter monitoring in a PLATO substudy revealed a higher incidence of asymptomatic ventricular pauses (≥3 seconds) in the first week of Ticagrelor therapy compared to clopidogrel. While the incidence of these pauses did not differ at 30 days, bradycardia and atrioventricular block have been reported, warranting caution in patients with underlying conduction system disease.
• Hyperuricemia: Ticagrelor can cause an increase in serum uric acid levels, which is generally reversible upon discontinuation. This has been associated with clinical reports of gout in a small number of patients.
• Thrombotic Thrombocytopenic Purpura (TTP): This is a rare but very serious condition that has been reported in postmarketing surveillance with Ticagrelor use. It is a medical emergency requiring prompt treatment.

6.4 Contraindications and Precautions

Based on its safety profile, Ticagrelor has several absolute contraindications and situations where it should be used with caution.

• Contraindications:
• History of intracranial hemorrhage
• Active pathological bleeding (e.g., active peptic ulcer)
• Severe hepatic impairment
• A history of hypersensitivity reaction (e.g., angioedema) to Ticagrelor or any of its components
• Precautions:
• Use with caution in patients at increased risk of bleeding, such as those with a history of bleeding disorders, recent major surgery or trauma, or moderate hepatic impairment.
• Use with caution in patients with underlying bradycardia, sick sinus syndrome (without a pacemaker), or a history of syncope.
• Use with caution in patients with a history of pulmonary disease, such as asthma or Chronic Obstructive Pulmonary Disease (COPD), as they may be more susceptible to the side effect of dyspnea.

Section 7: Drug and Food Interactions

The clinical use of Ticagrelor requires careful consideration of potential drug and food interactions, which are primarily driven by its metabolism via the CYP3A4 enzyme system.

7.1 Interactions via CYP3A4 Metabolism

The central role of CYP3A4 in the clearance of Ticagrelor makes it highly susceptible to interactions with drugs that inhibit or induce this enzyme.

• Strong CYP3A Inhibitors: Medications that strongly inhibit CYP3A4 (e.g., the antifungal agents ketoconazole and itraconazole; the macrolide antibiotic clarithromycin; and certain protease inhibitors like ritonavir) can significantly block the metabolism of Ticagrelor. This leads to a substantial increase in Ticagrelor plasma concentrations, which elevates the risk of bleeding and other adverse effects. The concomitant use of Ticagrelor with strong CYP3A inhibitors is not recommended and should be avoided.
• Strong CYP3A Inducers: Conversely, medications that are strong inducers of CYP3A4 (e.g., the anticonvulsants rifampin, carbamazepine, and phenytoin; and the barbiturate phenobarbital) can dramatically accelerate the metabolism of Ticagrelor. This leads to a significant reduction in Ticagrelor plasma concentrations and a loss of its antiplatelet efficacy, placing the patient at an increased risk of thrombotic events like MI or stroke. The concomitant use of Ticagrelor with strong CYP3A inducers should also be avoided.

7.2 Interactions with Other Medications

• Aspirin: As detailed in the boxed warning, maintenance doses of aspirin should be limited to 75-100 mg daily in ACS patients, as higher doses were associated with reduced Ticagrelor efficacy in a subgroup analysis.
• Simvastatin and Lovastatin: Ticagrelor is a moderate inhibitor of CYP3A4 and can therefore increase the plasma concentrations of other drugs that are substrates of this enzyme. This is particularly relevant for simvastatin and lovastatin. To mitigate the risk of statin-related adverse effects like myopathy, doses of simvastatin and lovastatin should not exceed 40 mg per day in patients taking Ticagrelor.
• Digoxin: Ticagrelor is also an inhibitor of the P-glycoprotein (P-gp) efflux transporter. Since digoxin is a P-gp substrate, co-administration with Ticagrelor can lead to increased digoxin levels. Therefore, monitoring of serum digoxin concentrations is recommended upon initiation or any change in Ticagrelor therapy.
• Opioids: In the acute setting, opioid analgesics (e.g., morphine) have been shown to delay and reduce the absorption of oral P2Y12 inhibitors, including Ticagrelor. This can result in lower plasma concentrations and diminished antiplatelet effect at a critical time. In patients receiving opioids, the use of a parenteral antiplatelet agent may be considered.
• Other Antithrombotic Agents: The concurrent use of Ticagrelor with other antiplatelet agents, anticoagulants (e.g., warfarin), or chronic nonsteroidal anti-inflammatory drugs (NSAIDs) will additively increase the risk of bleeding and should be undertaken with extreme caution and careful monitoring.

7.3 Drug-Food Interactions

• Grapefruit Juice: A significant food interaction exists with grapefruit and grapefruit juice. Grapefruit is a well-known strong inhibitor of intestinal CYP3A4. A study in healthy volunteers demonstrated that co-administration of grapefruit juice with Ticagrelor markedly increased its plasma concentrations and antiplatelet effects, more than doubling the drug exposure. This is due to the inhibition of first-pass metabolism in the gut wall. To avoid a potential increase in bleeding risk, patients taking Ticagrelor should be advised to avoid consuming grapefruit or grapefruit juice.
• Vitamin K-Rich Foods: Ticagrelor's mechanism of action is independent of the vitamin K-dependent coagulation cascade. Therefore, unlike the anticoagulant warfarin, there is no interaction with foods rich in vitamin K, such as leafy green vegetables (e.g., spinach, kale). Patients do not need to monitor or restrict their intake of these foods while on Ticagrelor therapy.

Table 7.1: Clinically Significant Drug Interactions with Ticagrelor and Management Recommendations

Interacting Agent/Class	Mechanism of Interaction	Clinical Consequence	Recommended Management	Source(s)
Strong CYP3A Inhibitors (e.g., ketoconazole, ritonavir)	Inhibition of Ticagrelor metabolism	Increased Ticagrelor exposure; increased bleeding risk	Avoid concomitant use
Strong CYP3A Inducers (e.g., rifampin, carbamazepine)	Induction of Ticagrelor metabolism	Decreased Ticagrelor exposure; reduced efficacy	Avoid concomitant use
Aspirin	Unknown; potential pharmacodynamic interaction	Reduced efficacy of Ticagrelor in ACS at high doses	Use maintenance dose of 75-100 mg daily
Simvastatin, Lovastatin	Inhibition of statin metabolism by Ticagrelor (CYP3A4)	Increased statin exposure; risk of myopathy	Avoid simvastatin/lovastatin doses >40 mg daily
Digoxin	Inhibition of digoxin efflux by Ticagrelor (P-gp)	Increased digoxin exposure; risk of toxicity	Monitor digoxin levels
Opioids (e.g., morphine)	Delayed/reduced absorption of Ticagrelor	Delayed onset of action; reduced efficacy	Consider parenteral antiplatelet agent in acute settings
Grapefruit Juice	Inhibition of intestinal CYP3A4 metabolism	Markedly increased Ticagrelor exposure; increased bleeding risk	Avoid concomitant consumption

Section 8: Dosing, Administration, and Regulatory Status

8.1 Dosing and Administration

The dosing regimen for Ticagrelor varies depending on the clinical indication and the phase of treatment. In all approved indications, it is co-administered with a daily maintenance dose of aspirin, which should be between 75 mg and 100 mg.

• For Acute Coronary Syndrome (ACS) or a History of MI:
• Treatment is initiated with a single 180 mg loading dose.
• This is followed by a maintenance dose of 90 mg taken twice daily for the first year following the ACS event.
• For long-term secondary prevention beyond one year in patients with a history of MI, the dose is reduced to 60 mg taken twice daily.
• For High-Risk Coronary Artery Disease (CAD) without prior MI/stroke:
• The recommended dose is 60 mg taken twice daily.
• For Acute Ischemic Stroke or High-Risk TIA:
• Treatment is initiated with a single 180 mg loading dose.
• This is followed by a maintenance dose of 90 mg taken twice daily for a duration of up to 30 days.

For patients who are unable to swallow the tablets whole, Ticagrelor tablets can be crushed into a fine powder, mixed with half a glass of water, and consumed immediately. The glass should then be rinsed with another half-glass of water and the contents consumed to ensure the full dose is administered. This administration option was approved by the FDA in 2015.

8.2 Regulatory History

Ticagrelor was developed by AstraZeneca and has undergone a strategic, evidence-driven expansion of its approved indications since its initial launch.

• Initial FDA Approval: Ticagrelor (as Brilinta) first received FDA approval on July 20, 2011. This approval was for reducing the rate of thrombotic cardiovascular events in patients with ACS, based on the positive results of the pivotal PLATO trial.
• Subsequent FDA Approvals:
• September 3, 2015: The FDA approved an expanded indication for the long-term use of Ticagrelor at a new 60 mg dose in patients with a history of heart attack. This approval was based on the findings of the PEGASUS-TIMI 54 study.
• June 1, 2020: The FDA approved Ticagrelor to reduce the risk of a first MI or stroke in high-risk patients with CAD. This indication was supported by the results of the THEMIS trial.
• November 6, 2020: Ticagrelor received approval to reduce the risk of stroke in patients with an acute ischemic stroke or high-risk TIA, based on the results of the THALES trial.

This regulatory timeline illustrates a classic pharmaceutical lifecycle management strategy. The drug was first established in a high-acuity, high-risk population (ACS) where its potent effects demonstrated a clear benefit over the standard of care. Following this success, its use was methodically expanded into chronic secondary prevention and other high-risk primary and secondary prevention populations as new, positive clinical trial data became available.

Section 9: Conclusion

Ticagrelor has established itself as a pivotal agent in antiplatelet therapy, representing a significant pharmacological advancement over the thienopyridine class of drugs. Its status as a direct-acting, reversibly binding P2Y12 receptor antagonist provides a more rapid, potent, and consistent antiplatelet effect compared to its predecessor, clopidogrel, while circumventing the limitations imposed by genetic variability in metabolic activation.

The clinical evidence, spearheaded by the landmark PLATO trial, has firmly established its superiority in the high-risk setting of acute coronary syndromes, where it significantly reduces the rates of cardiovascular death, myocardial infarction, and stent thrombosis. This benefit has been extended to long-term secondary prevention and to specific high-risk populations with coronary artery disease and acute ischemic stroke, supported by a robust program of large-scale clinical trials. However, the failure of the EUCLID trial to demonstrate a benefit in peripheral artery disease serves as a crucial reminder that the risk-benefit calculus of potent antiplatelet therapy is highly dependent on the specific vascular bed and disease acuity, and that clinical benefits cannot be universally extrapolated.

The pharmacological profile of Ticagrelor is a double-edged sword. Its unique secondary mechanism of inhibiting adenosine reuptake via ENT1 may contribute to its pleiotropic benefits, including the mortality reduction seen in PLATO, but it is also the likely cause of its most common non-bleeding side effect, dyspnea. Furthermore, its heavy reliance on CYP3A4 for metabolism makes it vulnerable to significant drug-drug interactions, necessitating careful medication reconciliation and avoidance of strong CYP3A inhibitors and inducers.

In conclusion, Ticagrelor is a highly effective antiplatelet agent for the prevention of atherothrombotic events in its approved indications. Its optimal use requires a nuanced understanding of its pharmacology, a thorough appreciation of the clinical evidence supporting its use in specific populations, and diligent management of its safety profile, particularly the ever-present risk of bleeding and its significant potential for drug interactions.

Works cited

1. US FDA approves expanded indication for BRILINTA to include long-term use in patients with a history of heart attack - AstraZeneca, accessed July 14, 2025, https://www.astrazeneca.com/media-centre/press-releases/2015/us-fda-approves-brilinta-long-term-use-heart-attack-history-patients-03092015.html
2. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist, accessed July 14, 2025, https://pubmed.ncbi.nlm.nih.gov/19604248/
3. Clinical Pharmacology Memorandum (BRILINTA) - FDA, accessed July 14, 2025, https://www.fda.gov/media/159528/download
4. Ticagrelor: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 14, 2025, https://go.drugbank.com/drugs/DB08816
5. Ticagrelor | C23H28F2N6O4S | CID 9871419 - PubChem, accessed July 14, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Ticagrelor
6. What is the mechanism of action of Ticagrelor (generic name for Brand name: Brilinta), a P2Y12 (Purinergic receptor P2Y12) inhibitor? - Dr.Oracle AI, accessed July 14, 2025, https://www.droracle.ai/articles/12331/ticagrelor-mechanism-of-action
7. Ticagrelor (oral route) - Mayo Clinic, accessed July 14, 2025, https://www.mayoclinic.org/drugs-supplements/ticagrelor-oral-route/description/drg-20075070
8. What is the indication for Brilinta (Ticagrelor)? - Dr.Oracle AI Medical Assistant, accessed July 14, 2025, https://www.droracle.ai/articles/31489/brilinta-
9. PLATelet inhibition and patient Outcomes - American College of ..., accessed July 14, 2025, https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2014/04/02/11/53/PLATO
10. Brilinta™ (ticagrelor) Tablets: A P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) - PMC, accessed July 14, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3353491/
11. Review of the Ticagrelor Trials Evidence Base - American Heart Association Journals, accessed July 14, 2025, https://www.ahajournals.org/doi/10.1161/JAHA.123.031606
12. Brilinta (ticagrelor) FDA Approval History - Drugs.com, accessed July 14, 2025, https://www.drugs.com/history/brilinta.html
13. Ticagrelor: an antiplatelet medicine to prevent blood clots - NHS, accessed July 14, 2025, https://www.nhs.uk/medicines/ticagrelor/
14. Ticagrelor (AR-C 126532XX, AZD 6140, CAS Number: 274693-27-5) | Cayman Chemical, accessed July 14, 2025, https://www.caymanchem.com/product/15425/ticagrelor
15. BRILINTA® (ticagrelor) tablets, for oral use - accessdata.fda.gov, accessed July 14, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022433s020lbl.pdf
16. Ticagrelor | CAS 274693-27-5 | SCBT - Santa Cruz Biotechnology, accessed July 14, 2025, https://www.scbt.com/p/ticagrelor-274693-27-5
17. 022433Orig1s000 - accessdata.fda.gov, accessed July 14, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022433Orig1s000ChemR.pdf
18. MI Completed Phase Trials for Ticagrelor (DB08816) | DrugBank Online, accessed July 14, 2025, https://go.drugbank.com/indications/DBCOND0021996/clinical_trials/DB08816?phase=&status=completed
19. Stroke, Ischemic Completed Phase 3 Trials for Ticagrelor (DB08816) | DrugBank Online, accessed July 14, 2025, https://go.drugbank.com/indications/DBCOND0059850/clinical_trials/DB08816?phase=3&status=completed
20. Ticagrelor | CAS 274693-27-5 - Tocris Bioscience, accessed July 14, 2025, https://www.tocris.com/products/ticagrelor_6864
21. Ticagrelor: MedlinePlus Drug Information, accessed July 14, 2025, https://medlineplus.gov/druginfo/meds/a611050.html
22. medlineplus.gov, accessed July 14, 2025, https://medlineplus.gov/druginfo/meds/a611050.html#:~:text=Ticagrelor%20is%20in%20a%20class,a%20heart%20attack%20or%20stroke.
23. Ticagrelor: agonising over its mechanisms of action - American Society of Hematology, accessed July 14, 2025, https://ashpublications.org/blood/article/128/23/2595/35695/Ticagrelor-agonising-over-its-mechanisms-of-action
24. Ticagrelor: An emerging oral antiplatelet agent - PMC, accessed July 14, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3643352/
25. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects - PubMed, accessed July 14, 2025, https://pubmed.ncbi.nlm.nih.gov/20551239/
26. What foods should I eat or avoid when taking Brilinta? - Drugs.com, accessed July 14, 2025, https://www.drugs.com/medical-answers/foods-eat-avoid-taking-brilinta-3536149/
27. www.drugs.com, accessed July 14, 2025, https://www.drugs.com/medical-answers/foods-eat-avoid-taking-brilinta-3536149/#:~:text=Your%20Brilinta%20(ticagrelor)%20dose%20can,as%20directed%20by%20your%20doctor.
28. In Progress: Ticagrelor Pathway, Pharmacokinetics - PharmGKB, accessed July 14, 2025, https://www.pharmgkb.org/pathway/PA166267821/components
29. Effect of CYP3A4∗1G and CYP3A5∗3 Polymorphisms on ..., accessed July 14, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5374142/
30. Annotation of FDA Label for ticagrelor and CYP2C19 - PharmGKB, accessed July 14, 2025, https://www.pharmgkb.org/labelAnnotation/PA166104851
31. Brilinta (ticagrelor): Side effects, cost, uses, and more - Medical News Today, accessed July 14, 2025, https://www.medicalnewstoday.com/articles/brilinta
32. A Comparison of Ticagrelor (AZD6140) and Clopidogrel in Patients With Acute Coronary Syndrome (PLATO) - ClinicalTrials.gov, accessed July 14, 2025, https://clinicaltrials.gov/study/NCT00391872
33. Ticagrelor Compared With Clopidogrel in Patients With Prior Lower Extremity Revascularization for Peripheral Artery Disease | Circulation - American Heart Association Journals, accessed July 14, 2025, https://www.ahajournals.org/doi/10.1161/circulationaha.116.025880
34. AstraZeneca reports top-line results from the Brilinta EUCLID trial in patients with peripheral artery disease, accessed July 14, 2025, https://www.astrazeneca.com/media-centre/press-releases/2016/astrazeneca-reports-top-line-results-from-the-brilinta-euclid-trial-in-patients-with-peripheral-artery-disease-04102016.html
35. Peripheral Artery Disease Treatment: Clopidogrel vs Ticagrelor - Michigan Medicine, accessed July 14, 2025, https://www.michiganmedicine.org/health-lab/aha-2016-ticagrelor-not-superior-pad
36. BRILINTA® (ticagrelor) tablets, for oral use - accessdata.fda.gov, accessed July 14, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/022433s037lbl.pdf
37. Label: TICAGRELOR tablet, film coated - DailyMed, accessed July 14, 2025, https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c4c1ca82-99bd-451a-ad77-7fe28c4ae3e8
38. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BRILINTA safely and effe - accessdata.fda.gov, accessed July 14, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/022433s035lbl.pdf
39. Ticagrelor Side Effects: Common, Severe, Long Term - Drugs.com, accessed July 14, 2025, https://www.drugs.com/sfx/ticagrelor-side-effects.html
40. Acute Coronary Syndrome (ACS) | BRILINTA® (ticagrelor) tablets, accessed July 14, 2025, https://www.brilinta.com/acs.html
41. Brilinta Interactions: Alcohol, Supplements, and More - Healthline, accessed July 14, 2025, https://www.healthline.com/health/drugs/brilinta-interactions
42. Challenging the FDA black box warning for high aspirin dose with ticagrelor in patients with diabetes - PubMed, accessed July 14, 2025, https://pubmed.ncbi.nlm.nih.gov/23431005/
43. Challenging the FDA Black Box Warning for High Aspirin Dose With Ticagrelor in Patients With Diabetes - PMC, accessed July 14, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3581224/
44. www.mayoclinic.org, accessed July 14, 2025, https://www.mayoclinic.org/drugs-supplements/ticagrelor-oral-route/description/drg-20075070#:~:text=This%20medicine%20may%20increase%20your,Avoid%20picking%20your%20nose.
45. Side Effects of Brilinta (ticagrelor): Interactions & Warnings - MedicineNet, accessed July 14, 2025, https://www.medicinenet.com/side_effects_of_brilinta_ticagrelor/side-effects.htm
46. www.goodrx.com, accessed July 14, 2025, https://www.goodrx.com/brilinta/interactions#:~:text=Brilinta%20(ticagrelor)%20is%20an%20antiplatelet,%2C%20carbamazepine%2C%20and%20certain%20statins.