Ticagrelor or Prasugrel Strategies in Acute Coronary Syndromes

Introduction

Acute coronary syndrome is an umbrella term for conditions associated with sudden, reduced oxygen supply to the heart provoked by disruption of an atherosclerotic plaque associated with inflammation, thrombosis, vasoconstriction and microembolisation. It encompasses unstable angina, and myocardial infarction with or without ST-segment elevation. The presence of ST-segment elevation or a new left bundle branch block are characteristic of a ST-segment elevation myocardial infarction (STEMI) resulting from a total occlusion of the affected artery and requiring immediate reperfusion therapy (thrombolysis or percutaneous coronary intervention). In contrast, treatment of non-ST-segment-elevation myocardial infarction (NSTEMI) or unstable angina aims to prevent progression to total occlusion of the artery.

Dual antiplatelet therapy, an ADP receptor antagonist and aspirin, has become a standard treatment for patients with an acute coronary syndrome. NICE guidelines recommend aspirin and clopidogrel. Ticagrelor is an alternative to clopidogrel, used together with aspirin in prevention of atherothrombotic events in patients with acute coronary syndrome. Alternatively, prasugrel can be used in combination with aspirin with the aim of preventing atherothrombotic events in patients with acute coronary syndrome undergoing primary or delayed percutaneous coronary intervention.

Cyclopentyl-triazolo-pyrimidine ticagrelor and thienopyridine prasugrel, antagonists of the P2Y12 subtype of ADP receptors on platelets, act as more effective platelet inhibitors than thienopyridine clopidogrel. Although both ticagrelor and prasugrel have received class I recommendation for treatment of patients with acute coronary syndromes, we do not have enough data to compare benefits and adverse effects of these drugs in treatment of patients with acute coronary syndrome for 1 year.

The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 trial was a clinical trial with the aim of comparing treatment strategies based either on ticagrelor or prasugrel in patients with acute coronary syndromes for whom invasive evaluation was planned.

Methods

Study design

Funded by the German Centre for Cardiovascular Research and Deutsches Herzzentrum München, this study was an investigator-initiated, phase 4, multicentre, randomized, open-label trial. The intention of this study was to compare the efficacy and safety of two antiplatelet drugs – ticagrelor and prasugrel in patients who were hospitalized for acute coronary syndromes and who were scheduled to undergo coronary angiography.

Did the trial address a clearly focused issue?
Yes. Clear primary and secondary outcomes were chosen.

Total of 4018 patients from clinical centres in Germany and Italy who were admitted with an acute coronary syndrome and for whom invasive evaluation was planned were enrolled.

Eligibility

Patients were eligible for the study if:

1. they were hospitalized for an acute coronary syndrome – ST-segment elevation myocardial infarction, non-ST-elevation myocardial infarction, or unstable angina,
2. and for which invasive evaluation was planned – patients were planned to undergo coronary angiography.

Patients were excluded if they:

1. did not meet inclusion criteria;
2. received oral anticoagulation;
3. had chronic renal insufficiency warranting dialysis;
4. received ticagrelor or prasugrel within 5 days before randomization;
5. had history of stroke, transient ischemic attack, or intracranial bleeding;
6. were previously enrolled in the trial;
7. were participating in another trial;
8. had other reasons.

Study protocol

Patients admitted with an acute coronary syndrome and awaiting coronary angiography were enrolled in each participating centre. Two groups of patients were created – one group received treatment with ticagrelor, whereas the second group was treated with prasugrel.

Was the assignment of patients to treatments randomized?
Yes. Computer-generated sequence in an opaque envelope for each patient was created at the coordinating centre and delivered to participating centres. Patients were treated either with ticagrelor or prasugrel, with a randomization ratio of 1:1.

Patients were given ticagrelor at a loading dose of 180 mg which was followed by a maintenance dose of 90 mg twice a day for 12 months. Prasugrel was administered at a loading dose of 60 mg and at a maintenance dose of 10 mg once a day for 12 months, with an exception of patients at the age of 75 and above or patients with a body weight of less than 60 kg who were given a reduced maintenance dose of 5 mg daily.

The loading dose of ticagrelor was given as soon as possible after randomization. Prasugrel was administered as soon as possible after randomization in patients with ST-segment elevation. In contrast, patients without ST-segment elevation were given prasugrel after diagnostic angiography and before percutaneous coronary intervention. Therefore, the loading dose was given to fewer patients in the prasugrel group compared to the ticagrelor group.

Patients admitted with ACS and awaiting coronary angiography:

Randomization:

1. Ticagrelor → 180 mg loading dose → 90 mg BD maintenance dose
2. Prasugrel
   • ST-segment elevation → 60 mg loading dose → 10 mg or 5 mg OD maintenance dose
   • no ST-segment elevation → diagnostic angiography → 60 mg loading dose → percutaneous coronary intervention → 10 mg or 5 mg OD maintenance dose

Were all of the patients who entered the trial properly accounted for at its conclusion?
Yes. 100 % of patients were evaluated for primary end point.

Aside from the experimental intervention, were the groups treated equally?
Yes.

Outcome measures

The primary outcome was the composite of death, myocardial infarction, or stroke within 12 months.

The secondary outcomes were:

1. incidence of major bleeding at 1 year, which was the safety end point, defined as type 3 to 5 on the Bleeding Academic Research Consortium (BARC) scale;
2. incidence of the individual components of the primary outcome at 1 year;
3. incidence of definite or probable stent thrombosis at 1 year.

BARC Definitions

Type 0	No bleeding
Type 1	Bleeding that is not actionable and does not cause the patient to seek treatment
Type 2	Any clinically overt sign of hemorrhage that “is actionable” and requires diagnostic studies, hospitalization, or treatment by a health care professional
Type 3	a. Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL (provided hemoglobin drop is related to bleed); transfusion with overt bleeding b. Overt bleeding plus hemoglobin drop < 5 g/dL (provided hemoglobin drop is related to bleed); cardiac tamponade; bleeding requiring surgical intervention for control; bleeding requiring IV vasoactive agents c. Intracranial hemorrhage confirmed by autopsy, imaging, or lumbar puncture; intraocular bleed compromising vision
Type 4	CABG-related bleeding within 48 hours
Type 5	a. Probable fatal bleeding b. Definite fatal bleeding (overt or autopsy or imaging confirmation)

McKeown, L. A. (2011). BARC: New Bleeding Definitions Aim to Standardize Trial Endpoints. TCTMD.com. Available at: https://www.tctmd.com/news/barc-new-bleeding-definitions-aim-standardize-trial-endpoints

Were all clinically important outcomes considered?
Yes.

Analysis

The intention-to-treat analysis was used to analyse data and all patients were included regardless the treatment received. However, the safety end point was analysed using a modified intention-to-treat analysis, including only patients who received at least one dose of either ticagrelor or prasugrel and were assessed for bleeding up to 7 days after the trial medication had been discontinued.

Primary and secondary outcomes were evaluated by the adjudication committee whose members were unaware of the trial-group assignments.

Were patients, health workers and study personnel ‘blind’ to treatment?
No. It was an open-label trial. Only the adjudication of end points was performed ‘blindly’.

Follow-up

Patients were followed-up at 30 days (± 10 days), 6 months (± 1 month) and 12 months (± 1 month).

Results

Population

23.8 % of enrolled patients were female and 76.2 % were male. Mean age was 64.5 in the ticagrelor group and 64.6 in the prasugrel group. Mean BMI was 27.8 in both groups.

Were the groups similar at the start of the trial?
Yes.

Primary outcome

A primary end-point event was:

1. death from any cause,
2. myocardial infarction,
3. or stroke within 1 year.

These occurred in 184 (9.1 %) patients in the ticagrelor group and in 137 patients (6.8 %) in the prasugrel group (hazard ration, 1.36; 95% confidence interval [CI], 1.09 to 1.70; P = 0.006).

The cause of death was cardiovascular disease, myocardial infarction or stroke in 161 (8.1 %) patients in the ticagrelor group and in 124 (6.3 %) patients in the prasugrel group (hazard ratio, 1.32; 95% CI, 1.04 to 1.66).

Secondary outcomes

	Ticagrelor group	Prasugrel group
Rate of death from any cause	4.5 %	3.7 %	(hazard ratio, 1.23; 95% CI, 0.91 to 1.68)
Incidence of myocardial infarction	4.8 %	3.0 %	(hazard ratio, 1.63; 95% CI, 1.18 to 2.25)
Incidence of stroke	1.1 %	1.0 %	(hazard ratio, 1.17; 95% CI, 0.63 to 2.15)
Incidence of definite or probable stent thrombosis	1.3 %	1.0 %	(hazard ratio, 1.30; 95% CI, 0.72 to 2.33)

Using the modified intention-to-treat analysis, major bleeding (BARC type 3 to 5) occurred in 5.4 % of patients in the ticagrelor group and in 4.8 % of patients in the prasugrel group (hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P = 0.46).

How precise was the estimate of the treatment effect?
Taking into account the wide confidence interval, the estimate of the treatment effect was made with low precision.

Can the results be applied to local population, or in your context?
Partially yes. On the one hand, the majority of the study population were men, we do not have any information about ethnicity of the study population and there is a high prevalence of stroke in the UK. On the other hand, the mean BMI of the study population was close to the mean BMI of the British citizens.

Discussion

Prasugrel was superior to ticagrelor in patients with invasively managed acute coronary syndrome because it significantly reduced the risk of ischaemic event without an increase in the rate of major bleeding.

How large was the treatment effect?
See above.

A primary end point event occurred in fewer patients in prasugrel group. This might be caused by lower incidence of myocardial infarction in this group compared to patients who were treated with ticagrelor.

One of the benefits of this trial is that it compared two antiplatelet treatment strategies rather than only two antiplatelet drugs. A prasugrel-based strategy (administration of a loading dose of prasugrel after diagnostic angiography in patients with acute coronary syndromes without ST-segment elevation) was found to be superior to ticagrelor-based strategy (administration of a loading dose of ticagrelor as soon as possible after randomization).

Limitations of this trial include open-label nature and unequal numbers of male and female patients. Moreover, patients with history of stroke, transient ischemic attack, or intracranial bleeding were excluded from the trial. Therefore, the secondary outcomes might not be completely applicable to the whole population.

Are the benefits worth the harms and costs?
Considering the low incidence of death, myocardial infarction, or stroke and low bleeding risk, the answer is yes.

Despite previously proved benefits of ticagrelor, such as in the Study of Platelet Inhibition and Patient Outcomes which favoured ticagrelor over clopidogrel in patients with an acute coronary syndrome, patients treated with prasugrel in this trial had lower incidence of death, myocardial infarction, or stroke than patients who received ticagrelor, without a significant difference in the incidence of major bleeding between these two groups.

References

Critical Appraisal Skills Programme (2018). CASP (Randomised Controlled Trial) Checklist. [online] Available at: https://casp-uk.net/wp-content/uploads/2018/03/CASP-Randomised-Controlled-Trial-Checklist-2018_fillable_form.pdf

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Bnf.nice.org.uk (2020). Acute coronary syndromes | Treatment summary | BNF content published by NICE. [online] Available at: https://bnf.nice.org.uk/treatment-summary/acute-coronary-syndromes.html

Bnf.nice.org.uk (2020). TICAGRELOR | Drug | BNF content published by NICE. [online] Available at: https://bnf.nice.org.uk/drug/ticagrelor.html

Bnf.nice.org.uk (2020). PRASUGREL | Drug | BNF content published by NICE. [online] Available at: https://bnf.nice.org.uk/drug/prasugrel.html

Nice.org.uk. (2011). Final appraisal determination | Ticagrelor for the treatment of acute coronary syndromes | NICE. [online] Available at: https://www.nice.org.uk/guidance/ta236/documents/acute-coronary-syndromes-ticagrelor-final-appraisal-determination-document2

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