THEMIS: Ticagrelor an option for selected T2DM patients with stable CAD
In patients with type 2 diabetes mellitus (T2DM) and stable coronary artery disease (CAD) without prior MI or stroke, ticagrelor plus low-dose aspirin significantly reduces ischaemic cardiovascular (CV) events vs aspirin alone, at the expense of increased major bleeding, with a favourable net clinical benefit observed in those with a history of percutaneous coronary intervention (PCI).
These results, from the phase III THEMIS and THEMIS-PCI trials presented at the European Society of Cardiology (ESC) Congress 2019 and World Congress of Cardiology (WCC) 2019, indicate that long-term therapy with ticagrelor plus aspirin would likely be of benefit for the subgroup of patients with high ischaemic risk and low bleeding risk who have previously tolerated dual antiplatelet therapy (DAPT) without bleeding complications, the investigators suggested.
The THEMIS trial included 19,220 patients (median age, 66 years) with T2DM who had been on antihyperglycaemic medications for ≥6 months and had stable CAD (ie, history of PCI, coronary artery bypass graft, or angiographic stenosis ≥50 percent in ≥1 coronary artery). Patients with known prior MI or stroke were excluded. [N Engl J Med 2019, doi: 10.1056/NEJMoa1908077]
The patients, recruited from 42 countries in North America, South America, Asia, Africa, Australia and Europe, were randomized 1:1 to receive low-dose aspirin (75–150 mg) plus ticagrelor or placebo. Ticagrelor was initially given at a dose of 90 mg BID, and subsequently at 60 mg BID based on tolerability data from the PEGASUS-TIMI 54 trial.
“Results of THEMIS showed a significantly lower incidence of the primary composite outcome of CV death, MI or stroke in the ticagrelor vs placebo group after a median follow-up of 39.9 months,” reported co-principal investigator Professor Deepak Bhatt of the Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, US.
At 36 months, the incidence of the primary efficacy outcome was 7.7 percent for ticagrelor vs 8.5 percent for placebo (hazard ratio [HR], 0.90; 95 percent confidence interval [CI], 0.81 to 0.99; p=0.04).
“However, the reduction in major ischaemic CV events was somewhat counterbalanced by a significant increase in Thrombolysis in Myocardial Infarction [TIMI] major bleeding, the primary safety outcome of the trial,” noted Bhatt.
The rate of TIMI major bleeding was 2.2 percent in the ticagrelor group vs 1 percent in the placebo group (HR, 2.32; 95 percent CI, 1.82 to 2.94; p<0.001). The rate of fatal bleeding was, however, not significantly different between the two groups (0.2 percent vs 0.1 percent; HR, 1.90; 95 percent CI, 0.87 to 4.15; p=0.11).
“In the prespecified subgroup patients with a history of PCI [n=11,154; 58 percent), the net clinical benefit of ticagrelor plus aspirin was more favourable,” said Professor Gabriel Steg of Hospital Bichat, Paris, France, senior author of the THEMIS-PCI trial. [Lancet 2019, doi: 10.1016/S0140-6736(19)31887-2]
In this subgroup of patients with a history of PCI, the relative risk reduction in CV death, MI or stroke was 15 percent (95 percent CI, 0.74 to 0.97; p=0.013) with ticagrelor vs placebo, compared with 2 percent (95 percent CI, 0.84 to 1.14; p=0.76) in those without a history of PCI.
TIMI major bleeding occurred in 2.0 percent vs 1.1 percent of PCI-treated patients in the ticagrelor and placebo groups (HR, 2.03; 95 percent CI, 1.48 to 2.76; p<0.0001), and in 2.4 percent vs 1 percent of patients without a history of PCI (HR, 2.79; 95 percent CI, 1.91 to 4.06; p<0.0001) (pinteraction; 0.20). The HR for fatal bleeding was 1.13 (95 percent CI, 0.36 to 3.50; p=0.83) in patients with a history of PCI compared with 3.04 (95 percent CI, 0.97 to 9.55; p=0.057) in those without a history of PCI (pinteraction=0.22).
“Ticagrelor significantly improved the net clinical benefit of irreversible harm, in terms of all-cause mortality, MI, stroke, and fatal bleeding or intracranial haemorrhage, in patients with a history of PCI [HR, 0.85; 95 percent CI, 0.75 to 0.95; p=0.0052],” reported Steg. “In these patients, 15.6 ischaemic events were prevented by the use of ticagrelor plus aspirin at the expense of 0.5 bleeding events.
“In contrast, no net clinical benefit with ticagrelor plus aspirin was observed in patients without a history of PCI [HR, 1.06; 95 percent CI, 0.93 to 1.21; p=0.39] [pinteraction=0.012],” he noted.
“These results suggest that long-term therapy with ticagrelor plus aspirin may be considered in patients with T2DM and a history of PCI who have tolerated antiplatelet therapy and have high ischaemic risk and low bleeding risk,” Steg concluded.
Of note, high rates of permanent treatment discontinuation were observed in both THEMIS (34.5 percent for ticagrelor vs 25.4 percent for placebo) and THEMIS-PCI (34.8 percent vs 25.7 percent). On-treatment analyses revealed HRs for the primary efficacy endpoint of 0.81 (95 percent CI, 0.71 to 0.92; p=0.001) and 0.73 (95 percent CI, 0.62 to 0.87; p=0.0003), respectively.