In late-breaking clinical trial results presented in a Hot Line Session at the European Society of Cardiology Congress 2019, investigators from Brigham and Women's Hospital and Greater Paris University Hospitals – AP-HP/Université de Paris presented the results from The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS), a clinical trial sponsored by AstraZeneca that evaluated whether adding ticagrelor to aspirin improves outcomes for patients with stable coronary artery disease and diabetes mellitus but without a history of heart attack or stroke.
Taking ticagrelor in addition to aspirin reduced the risk of a composite of cardiovascular death, heart attack, or stroke. Patients on this dual-antiplatelet therapy also experienced greater risk of major bleeding. In THEMIS-PCI, a study that specifically looked at THEMIS patients with a history of previous percutaneous coronary intervention (PCI) that includes stenting, versus the overall THEMIS population, investigators found even more favourable results for patients taking ticagrelor plus aspirin.
"With prolonged dual-antiplatelet therapy, we need to be thoughtful in considering which patients are most suited to taking the regimen – that is, those at high ischemic risk and low bleeding risk," said THEMIS co-chair Dr Deepak L Bhatt, executive director of Interventional Cardiovascular Programs at the Brigham and professor of medicine at Harvard Medical School. "Our findings show that the greatest benefit occurred in those patients with diabetes and stable coronary artery disease with a history of prior stenting for whom ticagrelor, when added to aspirin, reduced important cardiovascular events, such as heart attacks, strokes and amputations."
THEMIS co-chair Dr Philippe Gabriel Steg, chief of cardiology at Hôpital Bichat, Greater Paris University Hospitals – AP-HP, and professor at Université de Paris, stated, "The THEMIS population is a critically important one in which to understand the potential benefits of taking ticagrelor in addition to aspirin. As the number of people with diabetes continues to rise globally, we need to evaluate ways of improving long-term outcomes and preventing cardiovascular and ischemic events."
In THEMIS, the largest trial of patients with diabetes to date, more than 19,000 patients with stable coronary artery disease and diabetes were randomised to receive either ticagrelor plus aspirin or a placebo plus aspirin. Patients were followed for an average of more than three years. During that time, 736 of 9,619 patients (7.7%) taking ticagrelor plus aspirin experienced cardiovascular death, myocardial infarction, or stroke versus 818 of 9,601 patients (8.5%) taking placebo plus aspirin – 10% reduction.
As seen with other anti-platelet medications, ticagrelor increased the risk of major bleeding (206 patients versus 100 patients) and intracranial haemorrhage (70 patients versus 46 patients) compared with placebo. The difference in intracranial haemorrhages was driven by an increased number of traumatic bleeds, most of them subdural, and not by spontaneous or procedural bleeding.
Among participants with a history of previous PCI, the risk reductions outweighed the increased bleeding risks. Patients who had received PCI, which commonly uses devices known as stents to widen a coronary blood vessel and keep blood flowing, accounted for the majority (58%) of the total THEMIS population. Among these patients in THEMIS-PCI, 404 of 5,558 (7.3%) participants taking ticagrelor plus aspirin experienced cardiovascular death, myocardial infarction, or stroke, versus 480 of 5,596 (8.6%) participants taking placebo plus aspirin – a 15% reduction. Major bleeding occurred in 111 of 5,536 (2.0%) patients receiving ticagrelor and 62 of 5,564 (1.1%) patients receiving placebo. The risk for intracranial bleeding was similar between ticagrelor and placebo (33 patients versus 31 patients, respectively).
Ticagrelor provided a very favourable balance of benefit versus risk – more than in patients without a history of PCI.
"Our results indicate that among those with diabetes and stable coronary artery disease, we should focus on ticagrelor for patients with a history of prior stenting. This is an easily identifiable, logical sub-group," said Bhatt. "Studies currently support using long-term dual antiplatelet therapy for patients with acute coronary syndrome who are at high ischemic risk but low bleeding risk. Our work suggests that a much broader population of patients with stable coronary artery disease and diabetes stand to benefit substantially."
Background: Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear.
Methods: In this randomised, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. 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.
Results: A total of 19,220 patients underwent randomization. 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).
Conclusions: In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin.
P Gabriel Steg, Deepak L Bhatt, Tabassome Simon, Kim Fox, Shamir R Mehta, Robert A Harrington, Claes Held, Marielle Andersson, Anders Himmelmann, Wilhelm Ridderstråle, Maria Leonsson-Zachrisson, Yuyin Liu
[link url="https://www.brighamandwomens.org/about-bwh/newsroom/press-releases-detail?id=3421"]Brigham and Women’s Hospital material[/link]
[link url="https://www.nejm.org/doi/full/10.1056/NEJMoa1908077"]New England Journal of Medicine abstract[/link]