The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study - THEMIS

Contribution To Literature:

The THEMIS trial showed that ticagrelor/aspirin was associated with a reduction in cardiovascular events, with an increase in major bleeding compared with aspirin. 

Description:

The goal of the trial was to evaluate ticagrelor/aspirin compared with placebo/aspirin among patients with stable coronary artery disease and type 2 diabetes.


Study Design

  • Randomized
  • Parallel
  • Placebo

Patients with stable ischemic heart disease and type 2 diabetes were randomized to ticagrelor/aspirin (n = 9,619) versus placebo/aspirin (n = 9,601). Initially, patients received ticagrelor 90 mg twice daily; however, the study protocol was amended to 60 mg twice daily.

  • Total number of enrollees: 19,220
  • Duration of follow-up: 39.9 months
  • Mean patient age: 66 years
  • Percentage female: 32%
  • Percentage with diabetes: 100%

Inclusion criteria:

  • Stable ischemic heart disease (history of percutaneous coronary intervention [PCI] or coronary artery bypass grafting, or ≥50% stenosis in a major coronary artery)
  • Type 2 diabetes

Exclusion criteria:

  • History of myocardial infarction (MI) or stroke
  • Current treatment with dual antiplatelet therapy

Principal Findings:

The primary efficacy outcome of cardiovascular death, MI, or stroke occurred in 7.7% of the ticagrelor/aspirin group compared with 8.5% of group placebo/aspirin group (p = 0.04).

Secondary outcomes:

  • Cardiovascular death: 3.8% with ticagrelor/aspirin vs. 3.7% with placebo/aspirin (p = 0.79)
  • MI: 2.8% with ticagrelor/aspirin vs. 3.4% with placebo/aspirin (p < 0.05)
  • Stroke: 1.6% with ticagrelor/aspirin vs. 2.0% with placebo/aspirin (p < 0.05)

The primary safety outcome of TIMI major bleeding occurred in 2.2% of the ticagrelor/aspirin group compared with 1.0% of group placebo/aspirin group (p < 0.001).

Secondary outcomes:

  • Intracranial hemorrhage: 0.7% with ticagrelor/aspirin vs. 0.5% with placebo/aspirin (p = 0.005)
  • Bleeding leading to discontinuation of study medication: 4.9% with ticagrelor/aspirin vs. 1.3% with placebo/aspirin (p < 0.001)
  • Dyspnea leading to discontinuation of study medication: 6.9% with ticagrelor/aspirin vs. 0.8% with placebo/aspirin (p < 0.001)

The exploratory composite outcome of irreversible harm, all-cause death, MI, stroke, fatal bleeding, or intracranial hemorrhage occurred in 10.1% of the ticagrelor/aspirin group compared with 10.8% of placebo/aspirin group (p = not significant).

THEMIS-PCI substudy (n = 11,154 subjects with prior PCI):

The primary efficacy outcome of cardiovascular death, MI, or stroke occurred in 7.3% of the ticagrelor/aspirin group compared with 8.6% of group placebo/aspirin group (p = 0.013).

Secondary outcomes:

  • Cardiovascular death: 3.1% with ticagrelor/aspirin vs. 3.3% with placebo/aspirin (p = 0.68)
  • MI: 3.1% with ticagrelor/aspirin vs. 3.9% with placebo/aspirin (p = 0.027)
  • Stroke: 1.7% with ticagrelor/aspirin vs. 2.3% with placebo/aspirin (p = 0.024)

The primary safety outcome of TIMI major bleeding occurred in 2.0% of the ticagrelor/aspirin group compared with 1.1% of the placebo/aspirin group (p < 0.0001).

Secondary outcomes:

  • Intracranial hemorrhage: 0.6% with ticagrelor/aspirin vs. 0.6% with placebo/aspirin (p = 0.45)
  • The exploratory composite outcome of irreversible harm, all-cause death, MI, stroke, fatal bleeding, or intracranial hemorrhage occurred in 9.3% of the ticagrelor/aspirin group compared with 11.0% of the placebo/aspirin group (p = 0.005) (vs. those without prior PCI, p for interaction = 0.012).

Interpretation:

Among patients with stable ischemic heart disease and type 2 diabetes, ticagrelor/aspirin was associated with a reduction in major adverse ischemic events and an increase in major bleeding events compared with the placebo/aspirin group. More patients in the ticagrelor/aspirin arm discontinued study medication due to bleeding or dyspnea compared with the placebo/aspirin arm. An exploratory outcome of net irreversible harm occurred at a similar frequency between treatment arms. The TWILIGHT trial is testing a strategy of ticagrelor alone compared with aspirin alone in a similar population. In summary, ticagrelor/aspirin does not appear to have a favorable risk/benefit ratio among patients with stable ischemic heart disease and type 2 diabetes.

THEMIS-PCI substudy: Among patients with stable ischemic heart disease, type 2 diabetes, and prior PCI, ticagrelor/aspirin was associated with a reduction in major adverse ischemic events and an increase in major bleeding events compared with placebo/aspirin. An exploratory outcome of net irreversible harm occurred at a lower frequency in the ticagrelor/aspirin arm vs. the placebo/aspirin arm. In summary, among patients with stable ischemic heart disease, type 2 diabetes, and prior PCI, ticagrelor/aspirin appears to have a favorable risk/benefit ratio.

References:

Steg PG, Bhatt DL, Simon T, et al., on behalf of the THEMIS Steering Committee and Investigators. Ticagrelor in Patients With Stable Coronary Disease and Diabetes. N Engl J Med 2019;Sep 1:[Epub ahead of print].

Editorial: Bates ER. Antiplatelet Therapy in Patients With Coronary Disease and Type 2 Diabetes. N Engl J Med 2019;Sep 1:[Epub ahead of print].

Bhatt DL, Steg PG, Mehta SR, et al., on behalf of the THEMIS Steering Committee and Investigators. Ticagrelor in Patients With Diabetes and Stable Coronary Artery Disease With a History of Previous Percutaneous Coronary Intervention (THEMIS-PCI): A Phase 3, Placebo-Controlled, Randomised Trial. Lancet 2019;Sep 1:[Epub ahead of print].

Editorial Comment: Valgimigli M, Manavifar N. Ticagrelor in Patients With Diabetes and Previous PCI. Lancet 2019;Sep 1:[Epub ahead of print].

Presented by Dr. Deepak L. Bhatt at the European Society of Cardiology Congress, Paris, France, September 1, 2019.

THEMIS-PCI: Presented by Dr. Philippe Gabriel Steg at the European Society of Cardiology Congress, Paris, France, September 1, 2019.

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Clinical Topics: Anticoagulation Management, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Cardiac Surgery and SIHD, Interventions and Coronary Artery Disease, Chronic Angina

Keywords: ESC Congress, ESC 19, Adenosine, Anticoagulants, Angina, Stable, Aspirin, Constriction, Pathologic, Coronary Artery Bypass, Coronary Artery Disease, Diabetes Mellitus, Type 2, Dyspnea, Hemorrhage, Intracranial Hemorrhages, Myocardial Infarction, Myocardial Ischemia, Percutaneous Coronary Intervention, Primary Prevention, Stroke, Vascular Diseases


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