Ticagrelor-based DAPT may benefit select stable CAD patients with T2D
The addition of ticagrelor to aspirin significantly reduced ischaemic events but led to an upsurge in major bleeding events relative to aspirin alone in individuals with stable coronary artery disease (CAD) and type 2 diabetes (T2D) without prior myocardial infarction (MI) or stroke. However, there was a favourable net clinical benefit in a subgroup with prior percutaneous coronary intervention (PCI), according to the results of the THEMIS* and THEMIS-PCI trials presented at the ESC Congress 2019.
“This strategy of long-term dual antiplatelet therapy (DAPT) may be beneficial in select patients at low risk of bleeding but with a high risk of ischaemic events … Those who have previously tolerated DAPT without any bleeding complications seem to be the best candidates for prolonged therapy with ticagrelor and aspirin,” said THEMIS senior author Professor Deepak Bhatt from the Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, US.
In THEMIS, the incidence of the primary composite endpoint of cardiovascular death, MI, or stroke was 6.9 percent among ticagrelor recipients at 3 years, which was a significant drop from the 7.6 percent rate in the placebo arm (hazard ratio [HR], 0.90, 95 percent confidence interval [CI], 0.81–0.99; p=0.04). [ESC Congress 2019, abstract 2097]
The placebo rate is nearly identical to that observed in the placebo arm of PEGASUS-TIMI 54** in post-MI, nondiabetic patients, thus illustrating the high risk individuals with T2D and stable CAD apparently face, Bhatt pointed out.
However, the reduction in ischaemic events with ticagrelor was offset by the rise in TIMI*** major bleeding events vs placebo (2.2 percent vs 1.0 percent, HR, 2.32, 95 percent CI, 1.82–2.94; p<0.001), which contributed to high treatment discontinuation rates in both ticagrelor and placebo arms at 3 years (33.8 percent and 24.1 percent, respectively).
The on-treatment analysis conducted in view of the high withdrawal rates still revealed a significantly lower incidence of the primary efficacy outcome with ticagrelor vs placebo (5.2 percent vs 6.4 percent, HR, 0.81, 95 percent CI, 0.71–0.92; p=0.001). While this can provide insight into how a drug could have fared had there been higher adherence rates, this result must be interpreted cautiously as this may represent a best-case scenario ie, a patient is adherent to a drug and tolerating it well, noted Bhatt.
THEMIS comprised a large cohort of stable CAD patients with T2D (n=19,220, median age 66 years, 31 percent female, 58 percent with prior PCI) who were randomized 1:1 to receive twice-daily ticagrelor or placebo on a background of low-dose aspirin (75–150 mg). The initial 90-mg ticagrelor dose was reduced to 60 mg in view of the better tolerability profile of a lower dose reflected in PEGASUS-TIMI 54. [N Engl J Med 2019;doi:10.1056/NEJMoa1908077]
THEMIS-PCI, a prespecified subgroup analysis evaluating THEMIS patients with PCI history, also saw a significant drop in the incidence of the primary composite endpoint with ticagrelor vs placebo (6.5 percent vs 7.7 percent, HR, 0.85, 95 percent CI, 0.74–0.97; p=0.013) but a substantial rise in the incidence of TIMI major bleeding events (2.0 percent vs 1.1 percent, HR, 2.03, 95 percent CI, 1.48–2.76; p<0.0001). [ESC Congress 2019, abstract 2098]
However, the net clinical benefit of irreversible harm (composite of all-cause death, MI, stroke, fatal bleed, or intracranial haemorrhage) with ticagrelor vs placebo favoured the PCI arm as opposed to those without prior PCI (HR, 0.85, 95 percent CI, 0.75–0.95; p=0.005 [with prior PCI] vs HR, 1.06, 95 percent CI, 0.93–1.21; p=0.39 [without prior PCI]; pinteraction=0.012).
“This finding suggests that indeed, there is a different behaviour [between] patients with and without a history of PCI in terms of the benefit-risk ratio,” said Professor Philippe Gabriel Steg from the Hospital Bichat in Paris, France, senior author of THEMIS-PCI. “[Despite the] significant excess in TIMI major bleeding, it is reassuring that the patients in THEMIS-PCI had no significant increase in fatal or intracranial bleeding in terms of considering extended-duration ticagrelor.”
Nonetheless, Steg underlined that the findings cannot be generalized to all patients with stable CAD and T2D nor do these suggest that all PCI patients should necessarily receive ticagrelor. Ticagrelor may be a good addition to consider for reducing ischaemic risk in a select group of patients in this setting with insufficient response to aspirin, said Steg.
Despite the potential of this DAPT combination as a new therapeutic option in this setting, investigators of both trials underscored that the best antithrombotic approach beyond aspirin in patients with stable CAD remains unclear, hence the need for further investigation. “[H]ead-to-head trials of DAPT and double antithrombotic therapy with an antiplatelet drug plus a reduced-dose non-vitamin K oral anticoagulant [may be necessary].”
The increased bleeding rates in both trials also underline the value of evaluating individual risk of future ischaemic events and bleeding, noted the investigators. “Perhaps the best gauge of bleeding risk is whether they pass a bleeding stress test of having been on DAPT without sustaining a bleeding complication … [Moreover,] platelet function testing or other more global biomarker assessments of prothrombotic risks might help individualize treatment and guide which patients could benefit from antithrombotic intensification or de-escalation.”
Of note is the development of a ticagrelor reversal agent, which could be beneficial in managing serious bleeds in the future, said Bhatt. [N Engl J Med 2019;380:1825-1833]