Patients With CAD, Diabetes, Prior PCI See Most Benefit From Ticagrelor in THEMIS

Ticagrelor added to aspirin reduced ischemic cardiovascular events in patients with stable coronary artery disease (CAD) and type 2 diabetes (T2D), both with and without a history of percutaneous coronary intervention (PCI), but increased risk of major bleeding when compared with placebo, according to findings presented today at the European Society of Cardiology 2019 Congress in Paris, France.

Results from THEMIS (Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study), were simultaneously published in the New England Journal of Medicine¹, while data from a substudy, THEMIS-PCI, representing 58% of the patients with a history of PCI, were published separately in The Lancet.² While the studies revealed similar findings of lowered ischemic risk and increased major bleeding, the findings showed that patients with a history of PCI exhibited a nominally significant 15% net risk reduction (composite of benefits and irreversible harms) with ticagrelor, whereas non-PCI patients had an insignificant 6% net risk increase.³

THEMIS, a randomized, placebo-controlled, and double-blind study, examined patients age 50 or older, and who had stable CAD and T2D. The primary efficacy outcome was shown by a composite of cardiovascular death, myocardial infarction, or stroke, and tested major bleeding through thrombolysis in myocardial infarction (TIMI) criteria. As study authors led by Philippe Gabriel Steg, MD, and Deepak Bhatt, MD, MPH, note, it has been unclear whether patients with CAD and T2D who do not have a history of myocardial infarction or stroke will benefit from antiplatelet therapy. Authors of an accompanying commentary in The Lancet note that to this point, meta-analyses or short or prolonged dual antiplatelet therapy have largely examined aspirin with clopidogrel in patients with stable CAD and saw no benefit for patients taking therapy for an extended period.³

The full study examined 19,220 patients with a median follow-up of 39.9 months, with and without PCI history:

• Incidence of ischemic cardiovascular events was lower in the ticagrelor group (7.7% vs 8.5%; hazard ratio (HR) 0.90; 95% CI, 0.81-0.99; P = .04)

• Incidence of TIMI major bleeding was higher in ticagrelor group (2.2% vs 1.0%; HR 2.32; 95% CI, 1.82-2.94; P < .001) and also higher for intracranial hemorrhage (0.7% vs 0.5%; HR 1.71; 95% CI, 1.18-2.48; P = .005)

Fatal bleeding was not significantly different in the treatment and control group (0.2% vs 0.1%; HR 1.90; 95% CI, 0.87-4.15; P = .11), nor was the composite outcome of irreversible harm: all-cause death, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage (10.1% vs 10.8%; HR 0.93; 95% CI, 0.86-1.02). The substudy revealed comparable insignificant differences for the treatment and control groups in the proportion of patients with cardiovascular death (3.1% vs 3.3%; HR 0.96; 95% CI, 0.78-1.18; P = .68) and all-cause death (5.1% vs 5.8%; HR 0.88; 95% CI, 0.75-1.03; P = .11).

Patients With Prior PCI

THEMIS-PCI, a phase 3 substudy, examined 11,154 patients over a median follow-up of 3.3 years with previous PCI history. Similar to the full study, the incidence of ischemic cardiovascular events was lower in the ticagrelor group (7.3% vs 8.6%; HR 0.85; 95% CI, 0.74-0.97; P = .013), as was heightened major bleeding (2.0% vs 1.1%; HR 2.03; 95% CI, 1.48-2.76; P < .0001).

Authors of the substudy recommended that patients with previous PCI, high ischemic risk, and low bleeding risk should be considered under possible beneficiaries of ticagrelor. Patients who have undergone antiplatelet therapy, or received stents, without bleeding complications were additionally shown to benefit from ticagrelor if they remain at high ischemic risk.

In their commentary, Valgimigli and Manavifar caution that the THEMIS-PCI substudy is not independently powered and “should not be interpreted based on statistical inference for superiority in each study stratum,” meaning, patients with prior PCI vs those without prior PCI.

Nonetheless, they write, “Clinicians would now need to consider the combination of ticagrelor and aspirin as a new treatment option for patients with stable coronary artery disease and diabetes undergoing PCI.”³

Further studies into the risks and benefits of the drug combination are warranted to delineate optimal recipient groups, they wrote.

Ticagrelor is sold as Brilinta by AstraZeneca, which funded THEMIS and THEMIS-PCI.

References

1. Steg PG, Bhatt DL, Simon T, et al. Ticagrelor in patients with stable coronary disease and diabetes. [published online September 1, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1908077.

2. Bhatt DL, Steg PG, Mehta SR, et al. 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. [published online September 1, 2019]. Lancet. doi: 10.1016/S0140-6736(19)31887-2.

3. Valgimigli M, Manawifar N. Ticagrelor in patients with diabetes and previous PCI [published online September 1, 2019]. Lancet. doi.org/10.1016/S0140-6736(19)31887-2.