Clopidogrel plus Aspirin Use is Associated with Worse Long-Term Outcomes, but Aspirin Use Alone is Safe in Patients with Vasospastic Angina: Results from the VA-Korea Registry, A Prospective Multi-Center Cohort

Abstract

Anti-platelet agents are commonly used in vasospastic angina (VA) patients with comorbidity like coronary artery disease. However, long-term clinical outcomes in the use of aspirin, clopidogrel or the two agents together have rarely been investigated in VA patients. In a prospective study, we enrolled 2960 patients who received coronary angiography and ergonovine provocation test at 11 university hospitals in Korea. Among them, 1838 patients were diagnosed either with definite (n = 680) or intermediate (n = 1212) VA, using the criteria of chest pain, ECG changes and ergonovine provocation test results. They were analyzed according to their use of aspirin, clopidogrel or both, or no anti-platelet agent at all. The primary outcome was time to composite events of death from any cause, acute coronary syndrome (ACS) and symptomatic arrhythmia during a 3-year follow-up. A primary composite outcome was significantly more common in the aspirin plus clopidogrel group, at 10.8% (14/130), as compared with the non-antiplatelet group, at 4.4% (44/1011), (hazard ratio [HR] 2.41, 95% confidence interval [CI], 1.32-4.40, p = 0.004). With regard to the person-time event rate, similar results were shown, with the highest rate in the aspirin plus clopidogrel user at 4.72/1000 person months (95% CI, 2.79-7.96, log-rank test for primary outcome p = 0.016). The person-time event of the ACS rate was also highest in that group, at 2.81 (95% CI, 1.46-5.40, log-rank test for ACS p = 0.116). Kaplan-Meier survival analysis demonstrated poor prognosis in primary outcomes and ACS in aspirin plus clopidogrel users (log-rank test, p = 0.005 and p = 0.0392, respectively). Cox-proportional hazard regression analysis, adjusting for age, sex, history of coronary heart disease, hypertension, diabetes, presence or not of definite spasm, use of calcium channel blocker, demonstrated that the use of aspirin plus clopidogrel is an independent risk for the primary outcome (HR 2.01, CI: 1.07-3.81, p = 0.031). The aspirin-alone group had a similar primary and individual event rate compared to the no-antiplatelet agent group (HR 0.96, CI, 0.59-1.55, p = 0.872). Smokers using aspirin plus clopidogrel had poorer outcomes than non-smokers, with HR 6.36 (CI 2.31-17.54, p = 0.045 for interaction). In conclusion, among VA patients, aspirin plus clopidogrel use is associated with a poor clinical outcome at 3 years, especially in ACS. Aspirin alone appears to be safe for use in those patients.