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Can Patients with Stable Coronary Disease and Diabetes Benefit from Ticagrelor?

Dec 22, 2020
 
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Jonnessia Winslow, PharmD Candidate, South College School of Pharmacy

Cardiovascular events and diabetes go hand in hand, but what if there’s already a drug out there, Ticagrelor, to lower the risk of those events?  

Patients with stable coronary artery disease and diabetes mellitus who have not yet had a myocardial infarction or stroke are at high risk for cardiovascular events. Cardiovascular events are common among those with both coronary artery disease and type 2 diabetes mellitus. Patients with diabetes have increased platelet activation, thus leading to more ischemic events caused by Platelet-mediated thrombosis. With that being said, aspirin alone, which is standard therapy in this population, may not supply complete antithrombotic coverage. There are several P2Y12 antagonists on the market. However, ticagrelor, a reversible antagonist of the platelet P2Y12 receptor, has supportive data demonstrating more consistent platelet inhibition than aspirin or clopidogrel. Ticagrelor has also been shown to protect against cardiovascular events combined with aspirin in patients with acute coronary syndromes and high-risk patients with previous myocardial infarction. The relative benefit of ticagrelor in these patients has been consistent regardless of the presence of diabetes. Since patients with diabetes are at higher risk, they have had a sizeable absolute benefit from the addition of ticagrelor to aspirin.  

 

Whether patients with stable coronary artery disease and diabetes who did not have a history of myocardial infarction or stroke would benefit from dual antiplatelet therapy was unclear. Ticagrelor’s effect on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS) was designed to test the efficacy and safety of ticagrelor compared with placebo and aspirin in this population. 

This trial was a randomized, double-blind trial. Patients who were 50 years of age or older with stable coronary artery disease and type 2 diabetes mellitus could receive either ticagrelor plus aspirin or placebo plus aspirin. The presence of stable coronary artery disease was determined by any one of the following mutually nonexclusive criteria: a history of previous percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), or documentation of angiographic stenosis of at least 50% in at least one coronary artery. The receipt of an anti-hyperglycemic medication determined the presence of type 2 diabetes mellitus for at least six months. On the other hand, patients with previous myocardial infarction or stroke were excluded, as were those receiving dual antiplatelet therapy. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria. 

A total of 19,220 patients underwent randomization in a 1:1 ratio. Initially, patients were assigned to receive a ticagrelor dose at 90 mg twice daily or matching placebo. The protocol was amended and resulted in a reduction of ticagrelor dose to 60 mg twice daily due to a previous trial called PEGASUS–TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54). The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P=0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P=0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P=0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02) 

In conclusion, patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of significant bleeding vs. placebo plus aspirin.  

Practice Pearls: 

  • Patients with diabetes are at a greater risk of cardiovascular events. 
  • Ticagrelor is a P2Y12 antagonist with supportive data showing benefits combined with aspirin when given to patients with acute coronary syndromes and high-risk patients with previous myocardial infarction. 
  • Patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke who received ticagrelor and aspirin had a lower incidence of cardiovascular events. 

 

https://www.nature.com/articles/s41598-020-73871-x  

https://cardiab.biomedcentral.com/articles/10.1186/s12933-020-01153-x 

https://link.springer.com/article/10.1007/s40119-020-00197-0 

 

Jonnessia Winslow, PharmD Candidate, South College School of Pharmacy