Long-Term Therapy with Ticagrelor added to Low-Dose Aspirin PEGASUS-TIMI 54
N Engl J Med. 2015; 372:1791-1800 Presenter: Sheena Mathew Pharm.D.
Presentation Date: May 29,2015 Mentor: Carrie Oliphant, Pharm.D., BCPS-AQ-Cardiology
Article Summary: PEGASUS TIMI-54
Background:
Patients with myocardial infarction have a higher risk for recurrent ischemic events. A key pathophysiological element of cardiovascular ischemic events consists of the activated platelet. Use of dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor antagonist can help reduce the risk of ischemic events in the first year of acute coronary syndrome (ACS). Both the ACCF and ESC guidelines recommend dual antiplatelet therapy for up to 12 months post DES/BMS in an ACS patient. However, there is some conflicting data that an extended duration of DAPT may be beneficial in the continued reduction of ischemic events. Ticagrelor is a potent, reversibly binding, direct-acting P2Y12 receptor antagonist. The PLATO trial has showed a benefit with the use of ticagrelor and aspirin in the reduction of ischemic events and a mortality benefit in patients with ACS.
Objective:
To test whether long-term therapy with ticagrelor added to low-dose aspirin reduces the risk of major cardiovascular (CV) events among stable patients with a history of myocardial infarction (MI).
Study Design:
Randomized, double-blind, placebo-controlled clinical trial
Study Population:
Inclusion criteria / Exclusion Criteria-Spontaneous MI 1-3 years before enrollment
-Age ≥ 50 years
-one of the following additional high-risk features:
-Age ≥ 65 years
-Diabetes Mellitus requiring
medications
-A 2nd prior spontaneous MI
-Multivessel coronary artery
disease (CAD)
-Chronic renal dysfunction
(CrCl<60 ml/min) / -Planned use of P2Y12 receptor antagonist, dipyradamole, cilostazole, or anticoagulant therapy during the study period
-Bleeding disorder history
-History of ischemic stroke
-History of intracranial bleed
-Central nervous system tumor
-Gastrointestinal bleed within the previous 6 months
-Major surgery within the previous 30 days
-Renal failure requiring dialysis
-Concomitant use of potent inducer/inhibitor/substrate of CYP3A4
Endpoints:
Primary: Composite of CV death, MI, or stroke
Secondary:CV death and death from any cause
Composite endpoint of death from coronary
heart disease (CHD), MI, or stroke
Individual components of the composite
endpoints
Urgent coronary revascularization
Hospitalization for unstable angina
Transient ischemic attack (TIA)
Safety: Major bleeding based on the thrombolysis
Infarction (TIMI) definition
Intracranial hemorrhage
Fatal bleeding
Treatment: Aspirin 75-150 mg in conjunction with:
Arm 1 (n=7050): ticagrelor 90 mg twice daily
Arm 2 (n=7045): ticagrelor 60 mg twice daily
Arm 3 (n=7067): placebo
Results:
-Baseline Characteristics:
-Qualifying indications:
-Multivessel CAD~59%, History of PCI ~83%,STEMI
~53%,NSTEMI 41.1%
- >1 Prior MI~16%
-Years since MI-Median=1.7 years
-Aspirin at any dose ~99%
Endpoint / Placebo / Ticagrelor 90 mg / P-Value / Ticagrelor 60 mg / P-ValueCV death, MI or stroke / 9.04% / 7.85% / P=0.008 / 7.77% / P=0.04
Death from CHD, MI, or Stroke / 8.33% / 6.99% / P=0.002 / 7.09% / P=0.003
CV Death or MI / 7.81% / 6.79% / P=0.01 / 6.77% / P=0.01
Death from CHD or MI / 6.68% / 5.59% / p-0.004 / 5.75% / P=0.01
Death from CHD / 2.08% / 1.53% / P=0.02 / 1.72% / P=0.09
MI / 5.25% / 4.40% / P=0.01 / 4.53% / P=0.03
Stroke-Any / 1.94% / 1.61% / p-0.14 / 1.47% / P=0.03
Safety Endpoints:
TIMI Major / 1.06% / 2.60% / <0.001 / 2.30% / <0.001
TIMI Minor / 0.36% / 1.31% / <0.001 / 1.18% / <0.001
Transfusion / 0.72% / 2.43% / <0.001 / 2.09% / <0.001
Study-Drug-DC1 / 1.50% / 7.81% / <0.001 / 6.15% / <0.001
Dyspnea / 6.38% / 18.93% / <0.001 / 15.84% / <0.001
Gout / 1.51% / 2.28% / <0.001 / 1.97% / <0.01
1DC-Discontinuation
Conclusion:
The authors concluded that the addition of ticagrelor at a dose of 90-mg twice daily or 60-mg twice daily, to low dose aspirin reduced the risk of CV death, MI, or stroke and increased the risk of TIMI major bleeding among patients who had an MI 1-3 years.
Discussion:
In comparison to previous DAPT trials, including Trilogy-ACS, CHARISMA, and the DAPT trial the patients included in the study had mixed patient populations with various conclusions with the use of the extended duration of DAPT. Due to this conflicting data, there is still not a standardized decision on the exact patient population who would benefit from extended duration of DAPT.
Usage of extended combination therapy will come with the risk of bleed. When looking at the benefit versus the risk of DAPT for extended duration, the 90 mg dose had a NNT=84 and NNH=64, the 60 mg dose had a NNT=79 and NNH=81. Based on these results there is an increased risk of bleed in comparison to the benefit of the treatment. This would require more studies in order to assess the appropriate patient to utilize the extended duration of therapy.
Questions:
1. Patients were allowed to receive aspirin 75-150 mg daily. How was this allowed since we know the risk was increased beyond 100 mg?
Of the patients who were studied, 97% received the appropriate dose of 75-100 mg, due to this large percentage there would not be a significant difference in the patient population that received a higher dose. Although there were patients with the higher dose there was no subset analysis on these patients and their bleeding events.
2. How do you identify the patient potentially at risk for thrombotic events?
Patients at risk for thrombotic events could be patients with >1 myocardial infarction in their past medical history, hypercoaguable disorders, or patients with major coronary artery disease. Based on the CHARISMA trial, although there was no benefit in extended duration of DAPT, patients with “symptomatic” disease (patients with known cardiovascular disease) did have a benefit with the extended duration of DAPT. The PEGASUS-TIMI 54 trial showed that there was a decrease in the combined primary outcome of CV death, MI, or stroke; this was driven by the outcome of MI. The patient population in this study was patients with a history of MI, 1-3 years prior to starting the study, displaying a benefit in patients with a history of known coronary artery disease with a previous MI, these patients are at a higher ischemic risk and may benefit most from DAPT.
3. How to determine when the bleeding risk outweighs the benefit?
Patients with a history of bleeding disorders could potentially be affected by the bleed risk associated with extended duration of antiplatelet therapy versus the benefit. Along, with this patient population, patients who were on other antiplatelet agents (except for aspirin) and anticoagulation were excluded from the study. Based on this exclusion, it is unknown whether these patients on other types of antiplatelet/anticoagulation therapy would benefit from extended duration of DAPT. Also, patients with a lower ischemic risk will need to be assessed in order to understand if the risk would outweigh the benefit. In the PEGASUS TIMI-54 trial, 84 patients would need to be treated with 90-mg of ticagrelor in conjunction with aspirin to see a benefit, whereas 64 patients would need to be treated to see a harm (79 for benefit and 81 for harm for the 60-mg group). Therefore patients with a lower ischemic risk may be more at risk for harm then an actual benefit from utilization of extended DAPT.
4. The trial had an increase in dyspnea by 30% which was not seen in PLATO. Did they explain?
The increase in dyspnea in PEGASUS TIMI-54 could be due to the extended duration of ticagrelor use. The patients in PLATO were only followed for 12 months versus 3years in the PEGASUS TIMI-54 trial. The extended follow-up period could represent this increase in dyspnea seen in the study.
5. Given the different trial, which is your preferred agent of management?
Based on the data from the PEGASUS TIMI-54 trial the results for ticagrelor have shown a benefit in the combined endpoint of CV death, MI, or stroke with the use of ticagrelor 90 and 60 mg. Based on this data, I would be more inclined to utilize ticagrelor for extended DAPT. The CHARISMA trial did not show a benefit with the use of clopidogrel in patients with high-risk artherothrombotic events and the TRILOGY-ACS trial also did not show a benefit with extended duration of both prasugrel over clopidogrel in patients with unstable angina or MI without ST-elevations. Based on these results, the only agent that has shown a benefit with extended duration of DAPT is ticagrelor. However, since the patient populations were so different between the three trials, more trials with the other antiplatelet agents will need to be designed in order to assess their efficacy in the patient population studied in PEGASUS TIMI-54.
Trial / OutcomeDAPT / -Compared continued thienopyridine vs aspirin alone for 30 months
Statistically significant difference in the decrease of the primary outcome in the continued thienopyridine group:
•Stent-thrombosis
•MACCE: Death, MI
-Statistically significant increase in bleeding in the continued thienopyridine group (based on the GUSTO criteria and the BARC criteria)
TRILOGY-ACS / -Compared the use of DAPT with prasugrel vs. clopidogrel for 30 months in patients with unstable angina or MI without ST-segment elevation and did not undergo revascularization
-Prasugrel did not significantly reduce the primary endpoint of death from CV causes, MI, or stroke
-The incidence of bleeding occurred with similar frequency in both groups (based on the GUSTO criteria) in both age <75 years and overall population
-Slight increase in the prasugrel group in the TIMI criteria for major or minor bleed in patients <75 years of age
CHARISMA / -DAPT with clopidogrel + low-dose aspirin vs. aspirin alone in patients with high-risk atherthrombotic events
-There was no difference between the two groups in the primary efficacy end point of first occurrence of MI, stroke, or death from CV causes
-Statistically significant increase in moderate bleeding based on the GUSTO definition in the clopidogrel group vs. the placebo group
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