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AIMS To test the hypothesis that dobutamine stress echocardiography (DSE) reduces the rate of unnecessary invasive coronary angiography (CA) in patients with chronic stable coronary artery disease (CAD) and moderate to severe stenosis detected by coronary computed tomography angiography (CCTA). METHODS This study included 49 consecutive, symptomatic CAD patients with coronary lesions greater than 50% detected by CCTA who underwent all DSE and a CA with pressure wire evaluation and FFR measurement. The DSE operators was aware of the CCTA results, but invasive physicians were blinded to DSE results. The primary endpoint was the negative predictive value of a CCTA followed by a DSE test for detecting significant coronary artery disease (CAD). This was defined by the presence of significant coronary lesions (>90% stenosis) or moderate coronary lesions (50-90%) with abnormal FFR value of less than 0.80 evaluated by invasive angiogram (CA). Secondary endpoints included major adverse cardiovascular events (MACEs). RESULTS In patients with abnormal CCTA followed by CA, 33 patients (67.34%) had non-significant CAD lesions. In patients with both abnormal CCTA and DSE only 6 patients (12.24%) presented non-significant CAD. The negative predictive value of a CCTA followed by a DSE was significantly increased to 92.5%, when compared with CCTA alone. Thus DSE on top of abnormal CCTA could reduce unnecessary CA by 5.5 fold. During follow-up (mean 38.75 ± 12.25 months) 1 (2.1%) patient had a cardiac sudden death, 3 (6.12%) patients had an unplanned myocardial revascularization and 1 (2.1%) patient had a stroke, none of which occurred in patients with normal DSE. No patients experienced a myocardial infarction or needed un unplanned surgical revascularization. CONCLUSIONS The addition of DSE in case of abnormal CCTA increases significantly the negative predictive value for detecting significant CAD in need for revascularisation and thus reduces markedly the number of unnecessary CA. This diagnostic strategy has a higher diagnostic accuracy and negative predictive value to the opposite approach where an abnormal CCTA mandates a CA without additional functional testing.