Ticagrelor plus aspirin of clinical benefit in T2DM patients with stable CAD and prior PCI
THEMIS trial in T2DM patients with stable CAD
The phase III THEMIS trial included 19,220 patients (median age, 66 years; 31.4 percent female) with T2DM who had been on antihyperglycaemic medications for ≥6 months, and had stable CAD (ie, history of PCI or coronary artery bypass graft [CABG], or angiographic stenosis ≥50 percent in ≥1 coronary artery). Patients with 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 (23 percent), Africa, Australia and Europe, were randomized 1:1 to receive low-dose aspirin (75–150 mg) plus ticagrelor or placebo. The dose of ticagrelor was initially 90 mg BID and subsequently reduced to 60 mg BID during the trial based on emerging tolerability data from the PEGASUS-TIMI 54 study. [N Engl J Med 2015;372:1791-1800; J Am Coll Cardiol 2016;67:2732-2740; J Am Coll Cardiol 2016;67:1145-1154; Thromb Haemost 2017;117:940-947]
The primary efficacy outcome was a composite of CV death, MI or stroke. The primary safety outcome was Thrombolysis in Myocardial Infarction (TIMI) major bleeding.
Efficacy and safety outcomes
“At 36 months, the incidence of the primary efficacy outcome was significantly lower in the ticagrelor vs placebo group [7.7 percent vs 8.5 percent; hazard ratio (HR), 0.90; 95 percent confidence interval (CI), 0.81 to 0.99; p=0.04],” reported co-principal investigator, Professor Deepak Bhatt of the Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, US. [N Engl J Med 2019, doi: 10.1056/NEJMoa1908077]
“Subgroup analysis showed a generally consistent effect of ticagrelor vs placebo on the primary efficacy outcome,” said Bhatt.
A significant increase in TIMI major bleeding was also observed with ticagrelor vs placebo (2.2 percent vs 1.0 percent; HR, 2.32; 95 percent CI, 1.82 to 2.94; p<0.001).
As permanent treatment discontinuation was common in both groups (34.5 percent for ticagrelor vs 25.4 percent for placebo), an on-treatment analysis was performed on the primary efficacy endpoint. “Results showed a HR of 0.81 [95 percent CI, 0.71 to 0.92; p=0.001], favouring ticagrelor,” said Bhatt. “However, this finding should be interpreted with caution as on-treatment analysis reflects a best-case scenario of high adherence and tolerability.”
“Our results show that long-term dual antiplatelet therapy [DAPT] with ticagrelor plus aspirin may be beneficial in selected patients with T2DM and stable CAD without prior MI or stroke, who are at high risk of ischaemic events with a low risk of bleeding,” Bhatt concluded.
THEMIS-PCI trial in T2DM patients with stable CAD and PCI history
In patients with T2DM and stable CAD with a history of PCI, DAPT with ticagrelor plus aspirin is of clinical benefit, according to results of the THEMIS-PCI trial in a prespecified subgroup of THEMIS participants previously treated with PCI (n=11,154; 58 percent of overall THEMIS population). [Lancet 2019, doi: 10.1016/S0140-6736(19)31887-2]
“In THEMIS-PCI, 92.3 percent of the PCI-treated patients underwent the procedure with stenting. Drug-eluting stent was used in 61 percent of the PCI-treated patients,” said senior author Professor Gabriel Steg of Hospital Bichat, Paris, France. “The patients were followed up for a median of 3.3 years.”
Efficacy and safety outcomes
“Among patients with a history of PCI, a significant 15 percent relative risk reduction in the primary efficacy outcome of CV death, MI or stroke was observed with ticagrelor vs placebo [6.5 percent vs 7.7 percent; HR, 0.85; 95 percent CI, 0.74 to 0.97; p=0.013] at 36 months. In contrast, no significant reduction in the primary efficacy outcome was observed in patients with no history of PCI [7.4 percent vs 7.5 percent; HR, 0.98; 95 percent CI, 0.84 to 1.14; p=0.76] [pinteraction=0.16],” reported Steg. (Figure 1) [Lancet 2019, doi: 10.1016/S0140-6736(19)31887-2]
All-cause mortality, MI or stroke was also significantly reduced with ticagrelor vs placebo in patients with a history of PCI (8.9 percent vs 10.8 percent; HR, 0.82; 95 percent CI, 0.73 to 0.93; p=0.0014), but not in those without (10.5 percent vs 10.4 percent; HR, 1.02; 95 percent CI, 0.89 to 1.17; p=0.80) (pinteraction=0.021).
Similarly, all-cause mortality, MI, stroke, acute limb ischaemia, or major amputation of vascular aetiology was significantly reduced with ticagrelor vs placebo in patients with a history of PCI (9 percent vs 11 percent; HR, 0.82; 95 percent CI, 0.72 to 0.92; p=0.0007), but not in those without (10.5 percent vs 10.6 percent; HR, 1.00; 95 percent CI, 0.88 to 1.15; p=0.97) (pinteraction=0.023).
TIMI major bleeding occurred in 2.0 percent vs 1.1 percent (HR, 2.03; 95 percent CI, 1.48 to 2.76; p<0.0001) of patients with a history of PCI who were in the ticagrelor vs placebo group. In patients with no history of PCI, corresponding rates were 2.4 percent vs 1.0 percent (HR, 2.79; 95 percent CI, 1.91 to 4.06; p<0.0001) (pinteraction=0.20).
In THEMIS-PCI, 34.8 percent of ticagrelor recipients vs 25.7 percent of placebo recipients permanently discontinued treatment. On-treatment analysis revealed an HR for the primary efficacy endpoint of 0.73 (95 percent CI, 0.62 to 0.87; p=0.0003), favouring ticagrelor.
Net clinical benefit with ticagrelor in patients with PCI
A prespecified exploratory endpoint of THEMIS-PCI was net clinical benefit, defined as all-cause mortality, MI, stroke, fatal bleeding or intracranial haemorrhage in the intention-to-treat population.
Results of the net clinical benefit analysis showed an HR of 0.85 (95 percent CI, 0.75 to 0.95; p=0.0052), favouring ticagrelor, in patients with a history of PCI, compared with an HR of 1.06 (95 percent CI, 0.93 to 1.21; p=0.39) in patients with no history of PCI (pinteraction=0.012).
“Ticagrelor taken for 3 years could prevent 15.6 ischaemic events [p=0.002], while causing 0.5 bleeding events [p=0.79], for every 1,000 patients with a history of PCI ,” said Steg. (Figure 2)
“When the benefit of ticagrelor vs placebo was analyzed as a function of time from the most recent PCI to randomization, continued benefit of ticagrelor was observed for at least 6 years and possibly up to 10 years after PCI,” he added. (Figure 3)
“Results of THEMIS-PCI suggest that long-term therapy with ticagrelor plus aspirin is a new option for patients with T2DM and stable CAD with a history of PCI who have previously tolerated DAPT and have high ischaemic risk and low bleeding risk,” Steg concluded.