New PEGASUS-TIMI 54 sub-analyses provide direction on selecting patients most likely to benefit from long-term treatment with Brilinta (ticagrelor)

Additional data from PEGASUS-TIMI 54 post-hoc sub-analysis on long-term secondary prevention with ticagrelor irrespective of coronary stenting

12 November 2018

AstraZeneca presented new analyses from the PEGASUS-TIMI 54 trial at the American Heart Association (AHA) Scientific Sessions 2018 this weekend in Chicago, IL, USA 10-12 November, 2018. These findings help advance the clinical understanding of the role of dual-antiplatelet therapy in the treatment of post-MI patients beyond the initial 12 months of treatment for acute coronary syndrome (ACS).

These latest sub-analyses of the PEGASUS-TIMI 54 trial provide new data on a strategy to select patients for extended treatment with ticagrelor 60mg, who may derive greater reduction in major adverse cardiovascular events (MACE), with a lower absolute risk of major bleeding than the overall cohort in PEGASUS.¹ A second sub-analysis presented at the congress highlights the potential benefit of ticagrelor therapy in the long-term treatment of post-MI patients, irrespective of prior history of coronary stenting.²

Elisabeth Björk, Vice President, Head of Cardiovascular, Renal and Metabolism, Global Medicines Development at AstraZeneca said: “The studies presented during AHA reinforce the role that ticagrelor may play in reducing the persistent and long-term risk of cardiovascular events in patients with prior history of MI. Furthermore, these data offer additional tools to help clinicians identify the most appropriate patients for treatment”.

Highlights from the 14 ticagrelor abstracts presented at AHA include:

Long-Term Secondary Prevention with Ticagrelor for Prior Myocardial Infarction in Patients with No Coronary Stenting: a sub-analysis from PEGASUS-TIMI 54 (Oral Presentation 102 in Session AC.AOS.01 November 11, 2018, 4:15 PM - 4:25 PM S103bc)

A new post-hoc sub-analysis of the PEGASUS-TIMI 54 study examines the efficacy & safety of long-term treatment with ticagrelor in post-MI patients with vs. without a history of coronary stenting.

The PEGASUS-TIMI 54 trial randomized 21,162 patients with prior MI and additional high-risk factors to ticagrelor 60mg, 90mg (licensed for use up to the first 12 months) or placebo twice daily, on a background of low-dose aspirin therapy (75-150mg daily). There were 4,199 individuals with no history of coronary stenting at baseline enrolled in the trial. The relative risk reduction (RRR) in MACE with ticagrelor (pooled doses) was consistent in patients without (18% RRR) and with (15% RRR) prior coronary stenting (P for interaction = 0.95).² Given the higher baseline cardiovascular (CV) risk, patients without a history of coronary stenting demonstrated a higher absolute risk reduction in MACE (2.1% vs. 1.0%).²

These data indicate that long-term treatment with ticagrelor plus acetylsalicylic acid (ASA or aspirin) may be equally beneficial in reducing relative risk of MACE in patients with or without prior coronary stenting and indicates that the potential benefit of extended DAPT may be driven through reduction of new coronary atherothrombotic events, rather than stent protection alone.

Patient Selection for Long-Term Secondary Prevention with Ticagrelor: Insights from PEGASUS-TIMI 54 (Poster Presentation Session AC.APS.09 Nov 10, 2018 2:15 PM - 3:30 PM Sa2100 Zone 2)

A new post-hoc analysis of the PEGASUS-TIMI 54 trial explored whether clinical characteristics predicting bleeding and ischemic risk identify subgroups of patients who may derive greater reductions in the rate of MACE from long-term treatment with ticagrelor 60 mg, with a lower rate of major bleeding than the overall cohort in PEGASUS.

Included in the analysis were 13,938 patients assigned to either ticagrelor 60 mg plus ASA or ASA alone. Patients were grouped according to the presence or absence of predictors of bleeding events (anaemia at baseline and prior hospitalisation for bleeding) and ischaemic risk factors (recent P2Y12 inhibitor use < 1year, MI < 2years, multivessel coronary artery disease, diabetes mellitus, peripheral artery disease, chronic kidney disease or multiple prior MIs).

59% of patients had no predictors of bleeding events and at least 2 ischaemic risk factors. In these patients, ticagrelor 60mg significantly reduced the rate of MACE events by 1.9% (Number Needed to Treat = 52) whilst increasing the rate of major bleeding by 1.0% (Number Needed to Harm = 102).¹ In this subgroup ticagrelor also significantly reduced the risk of CV death (HR 0.66, p=0.0034, ARR 1.2%) and all-cause death (HR 0.75, p=0.018, ARR 1.1%).¹ The risk reduction in CV and all-cause death did not reach statistical significance when looking at the overall PEGASUS patient population without grouping patients according to risk predictors.   

19% of patients had a predictor of bleeding events. In these patients, treatment with ticagrelor 60mg did not reduce the MACE event rate vs ASA alone but did increase the rate of major bleeding by 2.2%.¹

22% of patients had no predictors of bleeding events and 0 or 1 ischaemic risk factors. In these patients, treatment with ticagrelor 60mg reduced the MACE event rate by 0.5% vs ASA alone, but increased rate of major bleeding by 1%.¹

In conclusion, a patient selection strategy excluding patients with predictors of bleeding and then stratifying based on number of ischemic risk factors may identify a large subgroup of patients (59%) with the potential to derive greater reductions in MACE from long-term treatment with ticagrelor 60mg, with a lower risk of bleeding than the overall cohort in PEGASUS.

Additional studies of note include:

The full list of highlighted AstraZeneca scientific presentations is available in our curtain raiser here, and the comprehensive list can be accessed on the AHA website here.

NOTES TO EDITORS

About PEGASUS-TIMI 54

PEGASUS-TIMI 54 (PrEvention with TicaGrelor of SecondAry Thrombotic Events in High-RiSk Patients with Prior AcUte Coronary Syndrome – Thrombolysis In Myocardial Infarction Study Group) is one of AstraZeneca’s largest outcomes trial with more than 21,000 patients from over 1,100 sites in 31 countries.⁵ The study assessed  (ticagrelor) tablets at either 60 mg twice daily or 90 mg twice daily plus once daily low-dose aspirin compared to placebo plus once daily low-dose aspirin for the secondary prevention of atherothrombotic events in patients ≥ 50 years of age who had experienced a heart attack one to three years prior to study start and had at least 1 risk factor for thrombotic cardiovascular events ( age ≥ 65 years, Diabetes mellitus requiring medication, at least one other prior MI, evidence of multivessel coronary artery disease or a creatinine clearance < 60 ml/min). The primary efficacy endpoint was a composite of cardiovascular (CV) death, myocardial infarction (MI) or stroke at 36 months. Patients were treated for at least 12 months and up to 48 months with a median follow-up time of 33 months. Ticagrelor 60 mg plus aspirin significantly reduced the primary composite endpoint of CV death, MI, or stroke by 16% RRR (ARR 1.27%) vs placebo plus aspirin at 3 years (Kaplan-Meier rates 7.77% vs 9.04% [HR: 0.84, 95% CI: 0.74–0.95]; P=0.0043).⁶ In PEGASUS, absolute rates of TIMI Major Bleeding were 1.7% for ticagrelor 60 mg plus aspirin vs 0.8% for placebo plus aspirin.⁷ Absolute rates of TIMI Major or Minor Bleeding rates were 2.4% for ticagrelor 60 mg plus aspirin vs 1.0% for placebo plus aspirin.⁷ Only the 60 mg dose is approved for use in patients with a history of MI beyond 12 months. The study was conducted in collaboration with the Thrombolysis in Myocardial Infarction (TIMI) Study Group from Brigham and Women’s Hospital (Boston, MA, USA).

About AstraZeneca in Cardiovascular, Renal & Metabolism

Cardiovascular, renal and metabolism is one of AstraZeneca’s main therapy areas and platforms for future growth. By following the science to understand more clearly the underlying links between the heart, kidney and pancreas, AstraZeneca is investing in a portfolio of medicines to protect organs and improve outcomes by slowing disease progression, reducing risks and tackling co-morbidities. Our ambition is to modify or halt the natural course of these diseases and even regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CVRM health for millions of patients worldwide.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. 

For more information, please visit www.astrazeneca.com and follow us on Twitter @AstraZeneca.

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References

1.   Bonaca MP, Storey RF, Bhatt DL, et al. Patient Selection for Long-Term Secondary Prevention with Ticagrelor: Insights from PEGASUS-TIMI 54; presented at: AHA Scientific Sessions 2018, 2018 Nov 10-12, Chicago, Illinois. http://www.abstractsonline.com/pp8/#!/4682/presentation/45643.

2.   Furtado RHM, Bhatt DL, Steg PG, et al. Long-Term Secondary Prevention with Ticagrelor for Prior Myocardial Infarction in Patients with no Coronary Stenting: a sub-analysis from PEGASUS TIMI 54; presented at: AHA Scientific Sessions 2018, 2018 Nov 10-12, Chicago, Illinois. http://www.abstractsonline.com/pp8/#!/4682/presentation/51815.

3.   Lindholm D, Erlinge D, Hasvold LP, et al. Impact of coronary artery disease severity on risk of cardiovascular events in type 2 diabetes patients: a swedish nationwide observational study [abstract]; presented at: AHA Scientific Sessions 2018, 2018 Nov 10-12, Chicago, Illinois. http://www.abstractsonline.com/pp8/#!/4682/presentation/50555.

4.   Marston N, Bonaca MP, Jarolim P, et al. High-sensitivity Cardiac Troponin at Any Detectable Concentration Identifies Higher Risk of Major Cardiovascular Events in Patients with Stable Ischemic Heart Disease [absrtact]; presented at: AHA Scientific Sessions 2018, 2018 Nov 10-12, Chicago, Illinois.

5.   U.S. National Institutes of Health. Prevention of Cardiovascular Events (eg, Death From Heart or Vascular Disease, Heart Attack, or Stroke) in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin (PEGASUS). [Identifier: NCT01225562]. https://clinicaltrials.gov/ct2/show/NCT01225562. Accessed October 17, 2018.

6.   Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372(19):1791-1800. doi:10.1056/NEJMoa1500857.

7.   European Medicines Agency. Brilique, INN-ticagrelor: European Public Assessment report EMA/CHMP/18297/2016. [Procedure No. EMEA/H/C/001241/0029/G]; 2016. https://www.ema.europa.eu/documents/variation-report/brilique-epar-assessment-report-variation_en.pdf. Accessed November 7, 2018.

^{Veeva ID: Z4-13733 | Date of preparation: November 2018 | Date of expiry: November 2020}