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DAPT Approach With Ticagrelor, Clopidogrel Demonstrate Efficacy Over Aspirin Alone

Although similar in reducing the risk of recurrent stroke, the use dual antiplatelet therapy with clopidogrel and aspirin was associated with a decreased risk of functional disability compared with ticagrelor and aspirin.

A recently conducted meta-analysis found no statistically significant difference of recurrent stroke or death at 90 days using a dual antiplatelet therapy (DAPT) approach of either ticagrelor (Brilinta; AstraZeneca) and aspirin or clopidogrel (Plavix; Sanofi) and aspirin; however, both were found to be superior to aspirin alone.1

Senior author Dar Dowlatshahi, MD, PhD, FRCP, stroke neurologist, University of Ottawa, and colleagues used data from 5 randomized clinical trials that enrolled patients with acute minor ischemic stroke or transient ischemic attack (TIA) and were treated with either of the 2 DAPT interventions within 72 hours of symptom onset, with a minimum follow-up of 30 days. The analysis aimed to see whether one of these treatment methods was superior in preventing recurrent strokes or death.

In total, 22,098 patients were included in the analysis, 5517 (24.9%) of which were on clopidogrel and aspirin, 5859 (26.5%) treated with ticagrelor and aspirin, and 10,722 (48.5%) on aspirin alone. At the end of the study, investigators concluded that both clopidogrel and aspirin (HR, 0.74 [95% Crl, 0.65-0.84]) and ticagrelor and aspirin (HR, 0.79 [95% Crl, 0.68-0.91]) were superior to aspirin alone in the prevention of the primary end point, although there was no statistically significant difference between the 2 treatment arms themselves (HR, 0.79 [95% Crl, 0.78-1.13]).

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"Our study suggests aspirin and ticagrelor is a reasonable alternative to aspirin and clopidogrel where there is clopidogrel failure or intolerance,” Lun and the other study authors concluded. They noted that as clopidogrel is a prodrug that requires enzyme activation by CYP2C19 to be converted to its active metabolite, resistance to the therapy may be high, but “resistance in the general population is highly variable in the literature, largely depending on the race and ethnicity of the population under study and definitions used. It is estimated that approximately 30% of the US population carries a loss-of-function allele for the CYP2C19 gene, and in Chinese populations, it may be as high as 60%. Despite this, clopidogrel and aspirin seems to be an effective therapy for stroke prevention even when tested in a predominantly Chinese population (eg, CHANCE trial), and therefore, the clinical significance of clopidogrel resistance remains unknown."

Treatment with clopidogrel and aspirin were associated with a lower risk of 90-day functional disability, a secondary outcome, compared with aspirin alone and compared with ticagrelor and aspirin (clopidogrel: HR, 0.82 [95% CI, Crl, 0.74-0.91]; ticagrelor: HR, 0.85 [95% Crl, 0.75-0.97]). Based on surface under the cumulative rank curve (SUCRA) values, clopidogrel and aspirin appeared to be the best treatment, with a SUCRA value of 0.99, compared with 0.01 for ticagrelor and aspirin and 0.0 for aspirin monotherapy.

Both of the DAPT interventions resulted in a significant increase in major hemorrhage compared with aspirin alone (clopidogrel: HR, 1.78 [95% Crl, 1.09-2.92]; ticagrelor: HR, 2.63 [95% Crl, 1.51-4.82]). Notably, aspirin was found to have the lowest risk of this outcome when observing SUCRA values (0.99), followed by clopidogrel and aspirin (SUCRA, 0.01) and ticagrelor and aspirin (SUCRA, 0.0).

Not only did neither DAPT regimen significantly increase the risk of hemorrhagic stroke compared to aspirin, but neither significantly differed from each other in the number of hemorrhagic strokes (HR, 0.67 [95% Crl, 0.26-1.70]). Ticagrelor and aspirin, with SUCRA values of 0.12, had the highest risk of hemorrhagic stroke.

A sensitivity analysis conducted at 30 days also indicated similar findings, with both clopidogrel and aspirin as well as ticagrelor and aspirin resulting in significant reduction of recurrent stroke or morality (clopidogrel: HR, 0.68 [95% Crl, 0.59-0.79]; ticagrelor: HR, 0.82 [95% Crl, 0.71-0.95]). Additionally, there was no significant difference when comparing the 2 DAPT interventions to each other (HR, 0.83 [95% Crl, 0.68-1.02]). Using SUCRA values, clopidogrel and aspirin were found to be associated with the lowest risk of recurrent stroke or death up to 30 days (SUCRA, 0.96), followed by ticagrelor and clopidogrel (SUCRA, 0.04) and aspirin (SUCRA, 0.0).

"Calculated probabilities using SUCRA plots revealed that ranking of the regimens assessed in the prevention of the primary outcome is as follows: clopidogrel and aspirin had the highest SUCRA value (ie, suggesting it is likely the best treatment), followed by ticagrelor and aspirin and aspirin monotherapy,” Lun et al wrote, although adding that these when based on SUCRA values, these rankings “should be interpreted with caution, particularly since comparisons of HRs across treatments were not significant for most secondary outcomes."

The FDA approved ticagrelor as a preventive treatment for patients with acute ischemic stroke or TIA in late 2020, expanding its previous indication beyond patients with cardiovascular disease. Data from the phase 3 THALES trial, which showed that aspirin plus 90-mg ticagrelor significantly reduced the rate of composite of stroke or death compared with aspirin alone, was the basis for the FDA’s decision. In that study, the DAPT approach reduced the primary composite end point by 17% (absolute risk reduction, 1.1%; hazard ratio [HR], 0.83; 95% CI, 0.71–0.96; P =.015) compared with aspirin alone.2

REFERENCES
1. Lun R, Dhaliwal S, Zitikyte G, Roy DC, Hutton B, Dowlatshahi D. Comparison of ticagrelor vs clopidogrel in addition to aspirin in patients with minor ischemic stroke and transient ischemic attack. JAMA Neurol. Published online December 6, 2021. Doi:10.1001/jamaneurol.2021.4514
2. Brilinta approved in the US to reduce the risk of stroke in patients with an acute ischemic stroke or high-risk transient ischemic attack. News release. AstraZeneca. November 6, 2020. Accessed December 20, 2021. https://www.astrazeneca-us.com/content/az-us/media/press-releases/2020/brilinta-approved-in-the-us-to-reduce-the-risk-of-stroke-in-patients-with-an-acute-ischemic-stroke-or-high-risk-transient-ischemic-attack-11062020.html