More Bleeding, Death With Ticagrelor Over Clopidogrel in Elderly Post-MI Patients: SWEDEHEART

Contrary to what has been observed in all-comers populations, new data from the SWEDEHEART registry on post-MI patients aged 80 or older show higher risks of bleeding and death with ticagrelor than with clopidogrel.

Until further studies are done, ticagrelor should be used cautiously in elderly patients, according to lead investigator Karolina Szummer, MD, PhD (Karolinska Institutet, Stockholm, Sweden), and colleagues. “There is a need for an adequately powered randomized study examining the effects of potent antiplatelets in the elderly population.”

The registry findings, which did show lower risks of new MI and stroke with ticagrelor, are in line with what was observed in the POPular AGE study, where clopidogrel held an advantage over more-potent antiplatelet agents for major and minor bleeding in NSTEMI patients 70 years or older. However, the new findings differ from those of PLATO and TRITON-TIMI 38, two trials that included younger patients. In PLATO, treatment with ticagrelor reduced the combined risk of death from vascular causes, MI, or stroke in patients with ACS with or without STEMI when compared with clopidogrel, while ACS patients treated with prasugrel in TRITON-TIMI 38 also had a reduced risk of ischemic events compared with clopidogrel, including stent thrombosis, but a greater risk of bleeding and fatal bleeding.

Commenting on the study for TCTMD, POPular AGE senior investigator Jurriën ten Berg, MD (St. Antonius Hospital, Nieuwegein, the Netherlands), said in an email that it provides further “evidence that the effect of strong P2Y12 inhibitors is different in elderly versus younger patients. We have to carefully evaluate the bleeding risk when choosing the best P2Y12 inhibitor, especially in elderly patients. In younger patients with no high bleeding risk, we can follow the guidelines and administer ticagrelor.”

He said the results from POPular AGE have changed practice since their initial presentation in 2019. “In many hospitals, clopidogrel is used in the elderly, especially when there is a high bleeding risk,” ten Berg observed, adding that the optimal antiplatelet combination to give to this cohort is generally aspirin plus clopidogrel. It’s possible, however, that the subgroup of elderly patients at low bleeding and high thrombotic risk, like those with multiple stents, bifurcation stenting, and diminished LV function, might benefit from more-potent antiplatelet therapy.

The data were published online ahead of print last week in Circulation and presented as an abstract during the virtual European Society of Cardiology Congress 2020.

Difference Observed in Elderly

For the study, the researchers included 14,005 MI patients (31.6% STEMI) 80 years or older who were enrolled in the SWEDEHEART registry between 2010 and 2017. Most (60.2%) were prescribed clopidogrel, but ticagrelor—which was introduced in 2012—increased in use from slightly over 20% that year to 72.5% in 2017.

After adjustment for age and baseline comorbidities, there were no significant reductions observed in the primary endpoint of death, readmission for MI, and stroke with and without bleeding for ticagrelor compared with clopidogrel. Within 1 year, those treated with ticagrelor were at lower risk of having a new MI (HR 0.80; 95% CI 0.70- 0.92) or stroke (HR 0.72, 95% CI 0.56-0.93), respectively, than those who received clopidogrel. But the ticagrelor-treated patients were more likely to die (HR 1.17, 95% CI 1.03-1.32) and to be rehospitalized for bleeding (HR 1.48, 95% CI 1.25- 1.76).

Notably, in the cohort of SWEDEHEART patients younger than 80 years, ticagrelor was associated with less MI (HR 0.82; 95% CI 0.75-0.91), stroke (HR 0.82; 95% CI 0.60-0.98), and death (HR 0.85; 95% CI 0.76-0.96) but more bleeding (HR 1.32; 95% CI 1.18-1.47) compared with clopidogrel. This equated to an overall 17% lower risk of ischemic events (HR 0.83; 95% CI 0.77-0.89) with ticagrelor but no difference in ischemic plus bleeding events (HR 0.95; 95% CI 0.89-1.01).

Szummer and colleagues write that this study was designed to resemble a clinical trial, especially by selecting patients at low risk for bleeding. “Except for age, which is a risk factor for bleeding, patients were excluded if they had anemia, prior bleeding, or new in-hospital bleeding events,” they explain. “Also, all patients were drug naive with regard to ticagrelor or clopidogrel on the index hospital admission. Yet, despite these stringent selection criteria, the risk of bleeding was higher among ticagrelor-treated patients.”

While the results seen here are “somewhat in contrast” with those of the PLATO trial, which showed no indications of an interaction between age and treatment, “it is important to note that patients included in clinical trials are very different from those in real-world clinical practice,” the authors stress. “But not all elderly are the same and several other factors influence the risk of bleeding, and high age is associated with high platelet reactivity and increased risk of thrombotic complications. Before we have more evidence from randomized trials, a more-individualized approach may be appropriate in the elderly.”

Other Options to be Explored

In an accompanying editorial, Piera Capranzano, MD, PhD (University of Catania, Italy), and Dominick J. Angiolillo, MD, PhD (University of Florida College of Medicine, Jacksonville), write that although the study is the largest to date showing higher mortality associated with ticagrelor over clopidogrel in the elderly and thus “provoking some uncertainties” regarding its use, some caution is warranted in interpreting the findings.

“First, although a propensity score-based technique was used to create a balanced population in which the treatment assignment is independent of measured confounders, and despite individuals extremely unlikely to be treated with ticagrelor were excluded, numerous uncontrolled variables known to impact mortality and bleeding could have influenced the higher risk with ticagrelor,” they write. “Indeed, the severity of coronary artery disease, type of intervention, concomitant comorbidities, and other factors specific to the elderly, including social, functional and cognitive, were not measured in SWEDEHEART. In the PLATO age subgroup analysis derived from a randomized data set, mortality was lower with ticagrelor compared with clopidogrel among the elderly, suggesting the need for a more risk-balanced comparison.”

It’s likely that some elderly patients may still benefit from more-potent antiplatelet therapy with ticagrelor, Capranzano and Angiolillo add. There are also techniques like shortened duration of dual antiplatelet therapy, de-escalation from ticagrelor to clopidogrel, and ticagrelor monotherapy after dropping aspirin that deserve to be studied in these patients.

“The optimal selection of an oral P2Y12 inhibitor (ticagrelor, low-dose prasugrel, or clopidogrel) in elderly patients post-MI should account for a multitude of factors that need to be weighed up, as this choice can make the difference,” they conclude.