Dyspnea-Related Ticagrelor Discontinuation After PCI
- Ticagrelor was discontinued due to dyspnea in 9.1% of patients with the majority of discontinuations occurring in the first 3 months after initiation.
- Independent predictors of ticagrelor discontinuation due to dyspnea included current smoking status, prior PCI, hypercholesterolemia, prior CABG, peripheral artery disease, BMI ≥30 kg/m2, Asian race (lower risk), and age ≥65 years old (higher risk).
- Ticagrelor dyspnea-related discontinuation was not associated with higher risk of subsequent ischemic events compared to ticagrelor plus aspirin in exploratory analysis.
What is the incidence and what are the outcomes and predictors of dyspnea-related ticagrelor discontinuation after percutaneous coronary intervention (PCI)?
TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) was a randomized, placebo-controlled trial of 9,006 patients at high ischemic or bleeding risk who underwent successful PCI with implantation of a drug-eluting stent. Key exclusion criteria included presentation with ST-segment elevation myocardial infarction (STEMI), cardiogenic shock, prior stroke, or need for oral anticoagulation. Patients were treated with open-label ticagrelor 90 mg twice daily and enteric-coated aspirin 81-100 mg daily for 3 months following PCI. Patients who were event-free and compliant with treatment at 3 months were randomized 1:1 in a double-blinded fashion to aspirin or placebo in addition to ticagrelor for an additional 12 months. All patients with dyspnea-related permanent ticagrelor discontinuation were included in this analysis irrespective of whether they switched to another oral P2Y12 inhibitor. Outcomes evaluated in this exploratory analysis included the incidence of dyspnea-related ticagrelor discontinuation, independent predictors of dyspnea, and the risk of ischemic and bleeding events following treatment discontinuation in patients randomized to ticagrelor monotherapy versus ticagrelor plus aspirin at 3 months post-PCI.
At 15-month follow-up, a total of 794 patients discontinued an antiplatelet agent (98.4% ticagrelor, 1.6% aspirin or matching placebo) due to dyspnea. Of those that discontinued ticagrelor, 4.6% restarted ticagrelor, 89.6% switched to another P2Y12 inhibitor, and 5.8% did not restart any P2Y12 inhibitor. A total of 745 (9.1%) patients were included in this analysis. More patients discontinued ticagrelor in the first 3 months than between 3 and 15 months after PCI (6.4% vs. 2.8%). Patients with dyspnea were older, with a higher body mass index, with more cardiovascular risk factors and comorbidities.
Independent predictors of dyspnea-related ticagrelor discontinuation included current smoking status, prior PCI, hypercholesteremia, prior coronary artery bypass grafting (CABG), peripheral artery disease, obesity, and advanced age. Age was the strongest predictor of dyspnea-related ticagrelor discontinuation (age 65-74 years: hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.43-2.03; age ≥75 years: HR, 2.25; 95% CI, 1.81-2.78). Asian race was associated with a lower risk of dyspnea-related ticagrelor discontinuation (HR, 0.25; 95% CI, 0.18-0.38). Ticagrelor monotherapy was associated with a lower rate of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding compared with ticagrelor plus aspirin (3.8% vs. 12.1%; p = 0044). There was no significant difference in the occurrence of death, MI, or stroke (5% vs. 7.1%; p = 0.566) or the composite of BARC type 3, 4, or 5 bleeding, death, MI, or stroke (8.8% vs. 17.2%; p = 0.1) between ticagrelor monotherapy compared to ticagrelor plus aspirin.
Dyspnea-related ticagrelor discontinuation occurred in 9.1% of patients and tended to occur earlier than late after PCI. Several demographic and clinical conditions predicted discontinuation and may be useful to identify patients at risk for therapy nonadherence.
The study of ticagrelor monotherapy warrants a closer examination of discontinuation related to dyspnea. Incidence of ticagrelor-related dyspnea has been reported between 14-21% with resulting discontinuation ranging from 0.9-6.5% of patients. Proposed mechanisms for dyspnea include upregulation of adenosine or via direct inhibition of P2Y12 receptors on neurons. TWILIGHT used a standardized algorithm to address dyspnea to promote adherence; despite these measures, a 9.1% discontinuation rate was observed. Identification of potential demographic and clinical conditions associated with increased risk for ticagrelor discontinuation may allow more timely identification and intervention in these vulnerable subgroups. No difference in ischemic events was observed in patients in the monotherapy arm who discontinued ticagrelor where most of these patients transitioned to clopidogrel.
Keywords: Acute Coronary Syndrome, Dyspnea, Percutaneous Coronary Intervention
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