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Keywords:

  • antiplatelet therapy;
  • clopidogrel;
  • platelet aggregation;
  • ticagrelor

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Ticagrelor: Mechanism of Action and Pharmacology
  5. Unresolved Mystery Regarding Ticagrelor Therapy and Safety
  6. Caution in Special Patient Populations
  7. Ongoing Research and Issues Related to Ticagrelor
  8. Conclusion
  9. Acknowledgement
  10. References
  1. Dual antiplatelet therapy is essential for the management of acute coronary syndrome. In particular, combination therapy using aspirin with a platelet ADP (i.e. P2Y12) receptor inhibitor, such as clopidogrel, prasugrel or, more recently, ticagrelor, has been recommended for patients with acute coronary syndrome.
  2. Pharmacological agents that reversibly inhibit platelet aggregation without metabolic activation in the liver are believed to reduce cardiovascular mortality compared with the current drug of choice for antiplatelet therapy, namely clopidogrel. These findings are based on a multicentre, double-blind, double-dummy, randomized controlled trial. Numerous factors are postulated to contribute to the improved survival of patients who take ticagrelor compared with those taking clopidogrel, including the risk of myocardial infarction, heart failure, arrhythmia and bleeding. In addition, clopidogrel may lead to a much higher incidence of infection. Although ticagrelor has recently been approved for use in the US and exhibits superiority over other antiplatelet agents, certain concerns remain regarding its use, including lung injury and dyspnoea, thus raising the issue of its true superiority over clopidogrel or prasugrel.
  3. Recent studies into ticagrelor report conflicting data, with certain aspects of its mechanisms of action still not fully understood. Ticagrelor has beneficial effects following its clinical application, such as achieving overall higher reductions in mortality compared with the use of clopidogrel and prasugrel. Harmful effects associated with the use of ticagrelor include a higher incidence of dyspnoea and major bleeding compared with clopidogrel.

Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Ticagrelor: Mechanism of Action and Pharmacology
  5. Unresolved Mystery Regarding Ticagrelor Therapy and Safety
  6. Caution in Special Patient Populations
  7. Ongoing Research and Issues Related to Ticagrelor
  8. Conclusion
  9. Acknowledgement
  10. References

Haemostasis is a finely regulated process that includes blood clotting, platelet activation and vascular repair.[1] Following vascular injury, the haemostatic system recruits an array of vascular and extravascular factors to coordinate with blood components to seal off damaged vessels. In this wound healing process, platelet activation and aggregation play pivotal physiological roles in tissue repair, although excessive platelet activation may account for thrombosis-related angiopathies. Not surprisingly, thrombotic events are rather common and contribute significantly to cardiovascular disease.[2] Moreover, many medical procedures, such as percutaneous coronary intervention (PCI) used to reduce mortality for acute coronary syndromes (ACS), can be complicated by potentially fatal stent thrombosis.[3] Given the important role of platelet activation in the pathophysiology of ACS, antiplatelet agents have become a mainstay of cardiovascular therapy in high-risk primary prevention and secondary prevention.[4] This is often achieved in a clinical setting using aspirin with a platelet ADP (i.e. P2Y12) receptor inhibitor as a secondary prevention, typically for 1 year after ACS diagnosis, especially after stent implantation.[4, 5] The P2Y12 receptor inhibitors include ticlopidine (rarely used), clopidogrel, prasugrel and ticagrelor, which was proven to reduce mortality in a multicentred, multicountry randomized controlled trial.[6] A thorough understanding of the newly approved antiplatelet agent ticagrelor is necessary and pertinent for decisions regarding the best therapeutic approach in patients with ACS.

Ticagrelor has demonstrated superiority over existing antiplatelet agents.[6] Despite these known benefits, some serious, albeit non-fatal, complications (e.g. dyspnoea and arrhythmia) have been reported in association with ticagrelor administration in the PLATelet inhibition and patient Outcomes (PLATO) trial.[6, 7] Numerous scenarios have been proposed to account for the adverse results observed specifically with ticagrelor treatment.[8, 9] Although the reduced mortality following coronary artery bypass graft (CABG) surgery reported for ticagrelor compared with clopidogrel may be due to fewer deaths from cardiovascular, bleeding and infectious complications, the precise mechanism of action underlying the reduction in mortality remains essentially unknown.[10-12] The aim of this minireview is to present the current hypotheses regarding the mechanisms underlying the beneficial effect of ticagrelor and to evaluate current research into the drug in order to provide a better understanding of future clinical perspectives. We do not focus on economic factors, such as cost and competing pharmaceutical interest, related to ticagrelor use.[13]

Ticagrelor is produced by Astra Zeneca (Wilmington, DE, USA) and is considered superior to the platelet inhibitors prasugrel (Effient, Eli Lilly, Indianapolis, IN, USA) and clopidogrel (Plavix; Bristol-Myers Squibb, New York, NY, USA) because both these drugs failed to provide an equal reduction in mortality compared with ticagrelor in the PLATO trial.[6] Ticagrelor superiority has also been reported in high-risk populations, such as patients with renal insufficiency and diabetes.[14-16]

For the present review, we conducted thorough investigations of reviews, clinical publications, US Food and Drug Administration (FDA) reports, empirical studies and editorials. This literature provided insights into the mechanisms underlying the conflicting clinical outcomes for ticagrelor. The following aspects were evaluated for each publication: (i) the purpose of the study; (ii) the definition of independent and dependent variables, if applicable, covariates, subanalyses, treatment arms, data sources and the validity and reliability of data collection; and (iii) clinical significance.[17]

Ticagrelor: Mechanism of Action and Pharmacology

  1. Top of page
  2. Summary
  3. Introduction
  4. Ticagrelor: Mechanism of Action and Pharmacology
  5. Unresolved Mystery Regarding Ticagrelor Therapy and Safety
  6. Caution in Special Patient Populations
  7. Ongoing Research and Issues Related to Ticagrelor
  8. Conclusion
  9. Acknowledgement
  10. References

To understand the controversy surrounding the recent findings for ticagrelor it is necessary to review its mechanism of action. Ticagrelor (formerly AZD-6140) is a reversible platelet antagonist that binds allosterically to the platelet ADP P2Y12 receptor.[18] In contrast, clopidogrel and prasugrel bind irreversibly to the receptor for the life of the platelet. In addition, unlike clopidogrel and prasugrel, ticagrelor does not need to undergo hepatic metabolic activation to assume an active form; therefore, it does not have the same pharmacogenetic limitations.[18-20] As more ticagrelor is metabolised into an inactive form, ADP binds to the receptor to initiate platelet activation (Fig. 1). The reversible nature of ticagrelor and its drug activity without the need for metabolism by the liver give it its unique pharmacological properties, including quick onset, quick response and short offset time.[21] Indeed, both in vitro and in vivo reports have confirmed that ticagrelor offers rapid, enhanced and maintained antiplatelet effects.[21-23] These properties offer considerable clinical benefit for ticagrelor, including a significant reduction in mortality related to cardiovascular events, myocardial infarction or stroke and a favourable safety profile. Key clinical trials to date for ticagrelor include: (i) the Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 versus clopidogrel in non-ST segment Elevation myocardial infarction (DISPERSE); (ii) DISPERSE-2; (iii) PLATO; (iv) Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of Ticagrelor versus Clopidogrel in patients with stable coronary artery disease (ONSET/OFFSET); and (v) Response to Ticagrelor in Clopidogrel Nonresponders and Responders and Effect of Switching Therapies (RESPOND) studies (see below). Although many promising studies have appeared in recent years that have contributed to the current understanding of the pharmacological effects of ticagrelor, only clinical trials that directly address clinically significant aspects of ticagrelor are highlighted in the present minireview.[19, 24-26]

image

Figure 1. Mechanism of action of ADP receptor antagonists. The ADP receptor antagonists (ticagrelor, clopidogrel and prasugrel) bind to the P2Y12 receptor, thereby inhibiting Ca2+ mobilization and activation of the platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptor. Inhibition of Ca2+ mobilization suppresses the release of arachidonic acid from the cell membrane and thromboxane A2 production, whereas reduced activation of the GPIIb/IIIa receptor prevents conformational changes that induce platelet aggregation. The ‘X’ endings indicate inhibition, whereas arrowheads denote stimulation. CYP, cytochrome P450.

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DISPERSE study

In the DISPERSE study, 200 patients with stable atherosclerosis were randomly allocated to receive 50, 100 or 200 mg ticagrelor twice daily, 400 mg ticagrelor once daily or 75 mg clopidogrel daily in addition to aspirin.[20] Patients were not included in the study if they had received recent anticoagulation therapy, were on current antiplatelet therapy other than aspirin, had undergone cardiovascular interventions, had ACS, were pregnant or had renal or hepatic failure. Platelet activity and the occurrence of adverse reactions were evaluated for 28 days. A significant increase in adverse effects was associated with once-daily 400 mg ticagrelor. The three higher doses of ticagrelor exhibited higher inhibition of platelet aggregation compared with clopidogrel (albeit with a ≥10% rate of dyspnoea). Overall, both drugs were associated with adverse events in at least 10% of patients. One incidence of major bleeding occurred with 400 mg ticagrelor once daily, which suggests why the approved dose of ticagrelor is 90 mg twice daily.

DISPERSE-2 and genetic polymorphism subanalysis

In the DISPERSE-2 study, 990 patients with non-ST segment elevation ACS received 75 mg clopidogrel once daily or 90 or 180 mg ticagrelor twice daily for up to 12 weeks in addition to aspirin.[27] Inclusion criteria were hospitalization for ACS-like conditions within 48 h of enrolment, more than 10 min ischaemic symptoms at rest and the presence of chemical markers for myocardial infarction or electrocardiographic signs of ischaemia. Half the patients in each ticagrelor group randomly received a loading dose of 270 mg ticagrelor. For patients undergoing PCI within 48 h of randomization, an additional 300 mg clopidogrel or placebo was given at the physician's discretion. The primary objective of that study was to evaluate total bleeding events (major and minor) within the first 4 weeks of treatment. Secondary outcomes included the incidence of myocardial infarction, death, stroke and severe recurrent ischaemia. The results revealed increased major bleeding events in the clopidogrel group within the first 48 h compared with both ticagrelor groups. Similar to the findings of the DISPERSE study, an approximate 4 and 10% higher incidence of dyspnoea was seen in both the 90 and 180 mg ticagrelor groups, respectively, compared with the clopidogrel group.[20, 27] An approximate 50% improvement in inhibition of platelet aggregation was noted with both doses of ticagrelor compared with the clopidogrel group, although the overall clinical outcomes remained largely similar.[26]

Both the DISPERSE and DISPERSE-2 trials were reanalysed to focus on genetic factors to evaluate the efficacy of ticagrelor versus clopidogrel in genetically predicted responders and non-responders to clopidogrel.[28] In that study, the researchers concluded that a cytochrome P450 (CYP) genetic polymorphism may not be able to significantly influence platelet inhibition in patients taking 90 or 180 mg ticagrelor twice daily. Clopidogrel has been reported to result in lower platelet inhibition among patients with CYP genetic polymorphisms, particularly CYP2C19 loss-of-function alleles.[29]

PLATO trial

The PLATO trial was a multicentre randomized double-blind controlled trial of 18 624 patients hospitalized for ACS with or without ST segment elevation and whose symptoms began within 24 h of enrollment.[6] Subjects with ACS and ST segment elevation were included in the trial if they met at least two of the three following criteria: (i) ST segment electrocardiographic changes signifying ischaemia; (ii) an indication of myocardial necrosis or risk factors (e.g. age > 60 years, previous myocardial infarction or CABG, coronary artery disease with two vessels > 50% stenosed, a history of ischaemic stroke, transient ischaemic attack, carotid stenosis > 50% or cerebral revascularization); and (iii) diabetes mellitus, peripheral arterial disease or chronic renal dysfunction. Those ACS patients with ST segment elevation had to need PCI and to have persistent ST segment elevation. Patients were excluded from the study if they could not take clopidogrel, had received fibrinolytic therapy at the beginning of the study, needed oral anticoagulation therapy, were at a greater risk of bradycardia or took potent CYP3A inhibitors or inducers. Patients in the study were randomly allocated to receive aspirin along with ticagrelor (180 mg loading dose; 90 mg twice daily maintenance) or clopidogrel (300–600 mg loading dose; 75 mg daily maintenance), using block randomization at each site, within 24 h of ischaemic symptoms and prior to any PCI procedure. After 12 months, the primary end-point (i.e. mortality resulting from vascular events) was significantly higher in patients taking clopidogrel compared with those taking ticagrelor. Dyspnoea, ventricular pauses and major bleeding occurred more frequently in the ticagrelor group; the controversy regarding the precise mechanism of action underlying these unfavourable outcomes remains.[6, 7]

A peculiar finding of the PLATO trial was perhaps the somewhat unfavourable result of the major end-point (mortality) in the North American arm of the trial. North America had approximately 1800 patients enrolled in the study. Although clopidogrel had a lower mortality hazard by 12 months, the overall data from all sites in the PLATO study yielded significantly superior results for ticagrelor. Even when excluding the larger sites outside North America, such as Hungary and Poland, ticagrelor still held a significant advantage in mortality over clopidogrel.[6] Three reasons may account for the inverse findings in the North American arm of the study: (i) an aspirin dose > 150 mg (in contrast with other treatment sites); (ii) a random act of chance; and (iii) more aggressive strategies used by clinical staff for pharmacological treatment.

An independent review was performed on data generated from the PLATO trial, citing discrepancies in clinical outcomes, such as mortality.[30] It was perceived that the mortality rates for clopidogrel were unexpectedly higher than reported in previous studies for that drug. Physicians from the PLATO trial refuted that claim, indicating that the reporting parameters and ethical conduct were appropriately chosen, reflecting integrity of the trial.[31, 32]

ONSET/OFFSET study

Ticagrelor was found to have a quicker onset and offset of action of inhibition of platelet aggregation compared with the irreversible P2Y12 receptor inhibitor clopidogrel in the PLATO trial, although further scrutiny is needed to adequately measure the validity of the observation in adult patients with stable coronary artery disease with concurrent aspirin therapy.[6, 33] Subjects excluded from the ONSET/OFFSET study included: (i) those with a history of ACS within 12 months of screening, congestive heart failure or left ventricular ejection fraction < 35%; (ii) candidates for antithrombotic therapy, such as warfarin, clopidogrel or aspirin doses > 100 mg daily; (iii) those with a forced expiratory volume below the normal range; (iv) those with severe pulmonary disease; (v) pregnant women; (vi) smokers; (vii) those using potent CYP3A inhibitors, inducers or substrates; (viii) those with a low platelet and/or haemoglobin count and glycosylated haemoglobin (HbA1c) > 10%; (ix) those with a medical history of drug addiction or alcohol abuse within the past 2 years; (x) those on concomitant non-steroidal anti-inflammatory therapy; or (xi) those with renal insufficiency.[33] Using higher loading doses for ticagrelor and clopidogrel and using similar maintenance doses in the PLATO study in addition to a high loading and maintenance dose of clopidogrel, the onset and offset of action of the two drugs plus placebo were evaluated. In all, 123 patients participated in the trial for 6 weeks, followed by an offset period of 10 days, during the first part of which a final maintenance dose of each drug was given. The onset and offset of action for both drugs (i.e. inhibition of platelet aggregation) were measured upon administration of the loading dose and last dose, respectively. The results revealed that the onset of maximal inhibition of platelet aggregation by ticagrelor was 5.8 h faster than that of clopidogrel, whereas both drugs maintained similar levels 24–48 h after the loading dose. For the offset of action, inhibition of platelet aggregation on Day 3 after the last dose of ticagrelor was similar to that on Day 5 after the last dose of clopidogrel. Comparable inhibition of platelet aggregation was seen on Days 5 and 7 for ticagrelor and clopidogrel, respectively.

The ONSET/OFFSET study allayed some concerns that missing a dose of ticagrelor (twice daily) may predispose a patient to an unacceptable increased risk of clotting. The patient would have to miss doses for a few days before the platelet aggregation protection would wear off. Conversely, ticagrelor does hold a 2-day advantage over clopidogrel if a patient undergoes surgery and the practitioner would like platelet aggregation activity to recover quickly. The onset of action of ticagrelor is not significantly quicker clinically (5.8 h) than that of clopidogrel and will likely not be factored in when choosing the appropriate antiplatelet agent for a given patient.

RESPOND study

The RESPOND study was an investigation of platelet aggregation inhibition in patients who had or had not responded to clopidogrel.[34] Another outcome was the occurrence of adverse events after switching to ticagrelor in a cross-over study format. The exclusion criteria for that study were similar to those of the ONSET/OFFSET study, although the term ‘smoking’ referred to those smokers who smoked more than one pack per day.[33, 34] Ninety-eight patients with stable coronary artery disease who had been treated originally with aspirin were recruited for the study.[34] The patients were screened for clopidogrel responsiveness and each group was randomized to receive either clopidogrel or ticagrelor for 14 days. The clopidogrel group received a 600 mg loading dose followed by a 75 mg daily maintenance dose. The ticagrelor group recieved a 180 mg loading dose followed by a 90 mg twice daily maintenance dose. After the first 14 day period, all the non-responder group and half the responder group switched therapy. Of all participants, 34 non-responders to clopidogrel and 54 responders completed the study. Responders and non-responders taking ticagrelor originally and those who switched to ticagrelor had greater inhibition of platelet aggregation, as well as increased bleeding and dyspnoea, compared with patients taking clopidogrel only. These findings favour the postulate that ticagrelor is an effective alternative for patients who do or do not respond to clopidogrel provided that adverse events, such as bleeding and dyspnoea, do not contraindicate treatment.

Unresolved Mystery Regarding Ticagrelor Therapy and Safety

  1. Top of page
  2. Summary
  3. Introduction
  4. Ticagrelor: Mechanism of Action and Pharmacology
  5. Unresolved Mystery Regarding Ticagrelor Therapy and Safety
  6. Caution in Special Patient Populations
  7. Ongoing Research and Issues Related to Ticagrelor
  8. Conclusion
  9. Acknowledgement
  10. References

The proposed mechanism behind the safety and superiority of ticagrelor over clopidogrel (and likely prasugrel) may be related to increased adensosine levels with tigarelor use.[7, 12, 13] Adenosine is associated with protective actions in the heart, such as improved pre- and post-conditioning, a reduction in infarct size and increased cardiomyocyte perfusion.[35] In addition to its antisclerotic attributes, the cytoprotective and anti-inflammatory actions of adenosine in ischaemic or stressed tissues should explain the relatively low mortality in the PLATO study. However, adenosine is known to trigger dyspnoea and neurocardiogenic syncope, which may result in mild or transient arrhythmias.[36, 37] A trial evaluating the positive and negative effects of ticagrelor regarding adenosine modulation in patients had a smaller sample size compared with the PLATO trial, although very similar outcomes were reported.[31] In contrast, dyspnoea is not likely associated with conventional non-reversible agents, such as aspirin or thienopyridines (ticlopidine, clopidogrel or prasugrel), suggesting a distinct mechanism of action underlying the shortness of breath seen after ticagrelor treatment.[8] The adenosine hypothesis offers a plausible explanation for such an adverse association. A recent study demonstrated that clinically significant promotion of adenosine occurs in patients who take ticagrelor.[31] Moreover, the reversible nature of platelet inhibition attributable to ticagrelor may lead to premature cell ageing, apoptosis and impaired turnover due to sequestration of overloaded and exhausted platelets in the pulmonary circulation.[8] These mechanisms may result in the development of a transfusion-related acute lung injury (TRALI)-like reaction and frequent dyspnoea. Although unfavourable complications such as dyspnoea and bleeding appear to be contributing factors in patients who discontinue therapy, no fatalities were reported as a result of the aforementioned adverse effects of ticagrelor. Patients experiencing dyspnoea should receive proper counselling so they may weigh the risks and benefits of ticagrelor treatment, especially patients with pulmonary comorbidities. These mechanisms hypothesized for the positive and negative effects of ticagrelor are plausible, but are yet to be validated.[12]

Caution in Special Patient Populations

  1. Top of page
  2. Summary
  3. Introduction
  4. Ticagrelor: Mechanism of Action and Pharmacology
  5. Unresolved Mystery Regarding Ticagrelor Therapy and Safety
  6. Caution in Special Patient Populations
  7. Ongoing Research and Issues Related to Ticagrelor
  8. Conclusion
  9. Acknowledgement
  10. References

Special populations, such as patients with diabetes or decreased renal function, may have disparate reactions to platelet inhibitors.[14-16] Patients with diabetes may have increased platelet reactivity and would be better matched with a more potent platelet inhibitor, such as prasugrel or ticagrelor.[15, 16] An experimental approach using diabetic rats indicated that ticagrelor is equally effective in reducing platelet aggregation in diabetic compared with non-diabetic populations.[16] Rat models may not adequately portray the effect of ticagrelor in humans with diabetes, so further studies are needed to confirm these findings, as well as to compare platelet inhibition between ticagrelor and other antiplatelet drugs.

Patients with decreased renal function may be at increased risk of myocardial infarction, as well as an increased risk of bleeding due to reduced clearance.[14] Renal impairment has minimal effects on systemic exposure to hepatically metabolized ticagrelor and its major active metabolite AR-C124910XX. Data from the PLATO trial were used to analyse subjects with renal impairment who took clopidogrel 75 mg daily or ticagrelor 90 mg twice daily. Outcomes of cardiovascular mortality or major bleeding did not differ clinically between groups treated with ticagrelor or clopidogrel.[14] This sub-study did not contain an equal number of subjects with renal insufficiency, evidenced as creatinine clearance < 60 mL/min in each group, which may have yielded skewed results.[14, 38] Choosing an antiplatelet agent based on impaired renal function may not be an appropriate method of patient care at present. Further research that is accurately powered to confirm the aforementioned results is needed to support this recommendation.

Ongoing Research and Issues Related to Ticagrelor

  1. Top of page
  2. Summary
  3. Introduction
  4. Ticagrelor: Mechanism of Action and Pharmacology
  5. Unresolved Mystery Regarding Ticagrelor Therapy and Safety
  6. Caution in Special Patient Populations
  7. Ongoing Research and Issues Related to Ticagrelor
  8. Conclusion
  9. Acknowledgement
  10. References

Astra Zeneca submitted a study notification in 2011 to the National Institutes of Health (NIH) announcing a trial of clopidogrel, prasugrel and ticagrelor in approximately 6000 patients naïve to the chosen drug prior to the study. Safety and efficacy will be evaluated for all three agents. This trial is entitled A Pharmacoepidemiological Study to Examine Patient Characteristics, Drug Utilization Pattern and Crude Incidence Rates of Selected Outcomes in New Users of Ticagrelor, Clopidogrel and Prasugrel in The Health Improvement Network (THIN) Database in the United Kingdom (UK) and should be completed by June 2013 (see http://www.clinicaltrials.gov/ct2/show/NCT01276275, accessed 1 May 2013). Observed outcomes include dyspnoeas, which may allow a true comparison of this side-effect among all agents and help health providers assess its clinical significance versus the primary outcome of mortality reduction.

According to a 2012 press release from Astra Zeneca (see http://www.businesswire.com/news/home/20120716006562/en/AstraZeneca-Initiate-Study-BRILINTA-Ticagrelor-Patients-PAD, accessed 2 May 2013), two large-scale clinical trials of ticagrelor are ongoing. An international clinical trial entitled PrEvention with TicaGrelor of SecondAry Thrombotic Events in High-RiSk Patients with Prior AcUte Coronary Syndrome–Thrombolysis In Myocardial Infarction Study Group (PEGASUS-TIMI 54) will evaluate cardiac event prevention in patients taking ticagrelor and aspirin concomitantly (see http://clinicaltrials.gov/show/NCT01225562, accessed 2 May 2013). That study is scheduled to conclude in early 2014 and will include over 20 000 subjects. Another ongoing study of ticagrelor includes the Examining Use of tiCagreLor In paD (EUCLID) study (see http://clinicaltrials.gov/ct2/show/NCT01732822, accessed 1 May 2013). In addition, the ‘Randomised, Double-blind, Double-dummy, Parallel Group, International (Asian), Multicenter, Phase 3 Study to Assess Safety and Efficacy of AZD6140 on Top of Low Dose Acetyl Salicylic Acid (ASA) Versus Clopidogrel on Top of Low Dose ASA in Asian/Japanese Patients With Non-ST or ST Elevation Acute Coronary Syndromes (ACS) for Whom PCI is Planned’ has been completed (see http://clinicaltrials.gov/ct2/show/NCT01294462, accessed 1 May 2013), although the results are not yet available. These investigations should be completed by mid-2013. Results from these Phase III clinical trials would likely broaden indications for ticagrelor, which should provide this P2Y12 receptor inhibitor an overwhelming advantage over other antiplatelet agents. However, it remains uncertain whether these trials will address the discrepancies discovered in the PLATO trial, such as ethnicity-related drug sensitivity and mortality reduction when ticagrelor is used in conjunction with low-dose aspirin.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Ticagrelor: Mechanism of Action and Pharmacology
  5. Unresolved Mystery Regarding Ticagrelor Therapy and Safety
  6. Caution in Special Patient Populations
  7. Ongoing Research and Issues Related to Ticagrelor
  8. Conclusion
  9. Acknowledgement
  10. References

In conclusion, ticagrelor may yield better outcomes for patients who qualify for antiplatelet therapy or those who do not respond to other antiplatelet agents, such as clopidogrel. Nonetheless, a precise mechanism with regard to clinical superiority has not been elucidated. A complete explanation for the inferior mortality reduction in patients taking ticagrelor versus those taking clopidogrel, as observed in the North American arm of the PLATO study, has not yet been proven. There is insufficient evidence to determine whether special populations may have lower cardiovascular mortality rates when treated with ticagrelor versus prasugrel or clopidogrel. More intensive research is warranted prior to the unanimous recommendation of ticagrelor.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Ticagrelor: Mechanism of Action and Pharmacology
  5. Unresolved Mystery Regarding Ticagrelor Therapy and Safety
  6. Caution in Special Patient Populations
  7. Ongoing Research and Issues Related to Ticagrelor
  8. Conclusion
  9. Acknowledgement
  10. References
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