By Jeffrey Zimmet, MD, PhD

Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center

Dr. Zimmet reports no financial relationships relevant to this field of study.

SYNOPSIS: In a study of 14,000 elderly patients with acute myocardial infarction, treatment with ticagrelor was associated with higher risks of bleeding and all-cause death vs. clopidogrel.

SOURCE: Szummer K, Montez-Rath ME, Alfredsson J, et al. Comparison between ticagrelor and clopidogrel in elderly patients with an acute coronary syndrome: Insights from the SWEDEHEART registry. Circulation 2020; Sep 1. doi: 10.1161/CIRCULATIONAHA.120.050645. [Online ahead of print].

What a difficult year it has been for ticagrelor. Ten years ago, the PLATO trial (Am Heart J 2009;157:599-605) demonstrated the superiority of ticagrelor over clopidogrel in patients with acute coronary syndromes. Those authors reported a decrease in all-cause death without an increase in the rate of overall major bleeding. Since then, ticagrelor has taken a significant share of the P2Y12 inhibitor market in acute coronary syndrome (ACS) based primarily on this trial data. Current guidelines specifically recommend using ticagrelor instead of clopidogrel in patients with myocardial infarction, unless it is contraindicated. Recent comparative data between the more-potent agents has not come out in ticagrelor’s favor. In late 2019, the ISAR-REACT 5 trial, designed to show the superiority of ticagrelor over rival prasugrel in ACS patients, showed just the opposite (N Engl J Med 2019;381:1524-1534).

Szummer et al raised more questions about the accepted superiority of ticagrelor over clopidogrel in this class of patients with ACS. This registry included data from all consecutive coronary care unit admissions in Sweden for symptoms suggestive of ACS. The authors compared the effects of ticagrelor and clopidogrel in an elderly population. They analyzed data from 14,005 patients who were age 80 years or older and presented to the hospital with a new diagnosis of MI between 2010 and 2017. This period encompassed the introduction of clopidogrel in 2011 and saw the use of ticagrelor increase from 0% to 72% of all ACS cases. Among the entire cohort, 8,434 were prescribed clopidogrel, while 5,571 were given ticagrelor. Fewer than one-third of all patients presented with STEMI, while the remainder carried diagnoses of non-STEMI.

Because patients prescribed ticagrelor were overall younger and presented with fewer comorbidities compared with the clopidogrel group, inverse probability treatment weighting (IPTW) was used to correct for differences in demographics and treatment. As expected, patients treated with ticagrelor were at lower risk for experiencing a new MI (HR, 0.80; 95% CI, 0.70-0.92) or stroke (HR, 0.72; 95% CI, 0.56-0.93). However, this occurred at the expense of a 17% higher risk of death (HR, 1.17; 95% CI, 1.03-1.32) and a 48% higher risk of hospitalization with a new bleeding event (HR, 1.48; 95% CI, 1.25-1.76). As a comparator, the authors analyzed the 58,671 patients in the registry younger than age 80 years. In this group, 62% were treated with ticagrelor, while 38% were given clopidogrel. Treating this younger group with ticagrelor was associated with a mortality benefit, in addition to lower risks of new MI and stroke vs. treatment with clopidogrel. However, there also was a 32% higher risk of new bleeding events. The authors concluded elderly patients presenting with acute MI, compared with younger patients, demonstrate differential safety and efficacy of ticagrelor. This translates to higher risks of bleeding and death compared with clopidogrel in this population. They recommend other researchers conduct a randomized trial that includes elderly patients to guide future therapy.

COMMENTARY

The observational, retrospective SWEDEHEART carries all the limitations that design suggests. Despite those limitations, this is by far the largest investigation of its kind and was well-done. Among younger patients, ticagrelor showed similar benefits to what had been seen in PLATO, in which the average age of subjects was only 62 years. This suggests a validity to these methods when compared with randomized, controlled trials performed in this space. Bleeding itself clearly also was more common in ticagrelor-treated patients vs. clopidogrel-treated patients in the younger cohort (HR, 1.32). However, the risk of all-cause death was lower. The fact that younger patients showed a similar ticagrelor-related hazard of bleeding but opposite effects on all-cause death suggests a differential effect of bleeding itself in elderly patients. Current guideline recommendations in both the United States and Europe suggest preferential use of the more potent P2Y12 inhibitors ticagrelor and prasugrel over clopidogrel in treatment of ACS, without respect to age or other comorbidities. Real-world patients often are older, and the best therapy may vary for different patient subsets. Elderly patients are common; in this registry, just under 20% of all MI patients were older than age 80 years. Approximately one-third of MI patients in similar registries are older than age 75 years. In this study, age alone, without respect to other recognized risk factors for bleeding, was enough to tilt the risk:benefit balance of ticagrelor.

It is worth noting that among patients older than age 80 years in SWEDEHEART, clopidogrel was used in most cases, whereas in younger patients the proportions are reversed (~60% clopidogrel use in the older than age 80 years population vs. ~60% ticagrelor use in younger patients). Clearly, there already is some recognition of the hazards of more potent antiplatelet agents in the elderly. For now, despite current guidelines, cardiologists should not take a one-size-fits-all approach in the treatment of ACS and should consider the potential downside of more potent antiplatelet agents in older patients.