Background <p>The chronic obstructive pulmonary disease (COPD) guidelines recommend selecting initial treatment based on the severity of respiratory symptoms or exacerbation history. However, some patients still experience clinically important deterioration (CID) despite this strategy. Therefore, we aimed to identify the risk factors to guide initial treatment, focusing on mild-to-moderate COPD patients whose annualized CID cannot be controlled by a single-bronchodilator.</p> Methods <p>Patients in the tiotropium group from a randomized controlled trial were included. Over 2 years, annualized CID was defined as forced expiratory volume in one second (FEV₁) decline at least 100 ml, COPD assessment test (CAT) increasing at least 2 points, or having experienced at least two moderate or one severe acute exacerbations of COPD (AECOPD) in this study. Random coefficients model within a bayesian framework was adapted to estimate the change in FEV₁ and CAT scores. The logistic regression analysis was adapted to detect the risk factors. The risk of annualized CID was evaluated using the incidence risk ratio (IRR) for patients with risk factors.</p> Results <p>Of 312 patients with mild-to-moderate COPD receiving tiotropium, 29.2% still experienced annualized CID. The proportions of patients who developed annualized CID regarding FEV₁, CAT, and AECOPD was 20.5, 8.0, and 6.1%, respectively. Post-bronchodilator FEV₁:FVC ≤ 60% (OR = 1.73, 95%CI: 1.06–2.84) and smoking pack-years ≥50 (OR = 1.95, 95%CI: 1.11–3.41) were associated with higher risk of experiencing annualized CID. The IRR of annualized CID was increased with more risk factors at baseline.</p> Conclusion <p>Patients with more prominent airflow limitation and higher smoking pack-years warrant intensified initial treatment to control their annualized CID.</p>