Introduction: While single-photon emission computed tomography (SPECT) V/Q has been widely adopted for pulmonary embolism (PE) diagnosis, it is not currently endorsed by clinical guidelines due to insufficient evidence.

Methods: We conducted a non-inferiority randomised trial comparing SPECT V/Q, computed tomography pulmonary angiography (CTPA), and planar V/Q-based diagnostic strategies using a 2:1:1 allocation. The primary endpoint was the 3-month risk of venous thromboembolism (VTE) in untreated patients with a negative work-up, comparing SPECT V/Q to the combined CTPA and planar V/Q arms. A non-inferiority margin of 1% absolute difference in 3-month VTE risk was defined. Secondary outcomes included PE diagnosis rates. The trial ended prematurely in October 2024 due to slow recruitment and funding limitations.

Results: From July 2017 to October 2024, 603 patients were randomised. PE was diagnosed in 61/303 (20.1%) in the SPECT V/Q arm, 31/150 (20.7%) in the CTPA arm, and 24/150 (16.0%) in the planar V/Q arm. The 3-month VTE risk in patients left untreated after a negative work-up was 0.5% (1/221) for SPECT V/Q, 0.0% (0/107) for CTPA, and 0.8% (1/118) for planar V/Q. The difference in outcome between SPECT V/Q and the combined arms was 0.0% (95%CI -1.2% to 1.3%; p for non-inferiority=0.75).

Conclusion: After being prematurely discontinued, this randomised trial did not demonstrate the non-inferiority of a SPECT V/Q-based strategy to reference standards for PE diagnosis. However, the results suggest a low 3-month VTE risk in patients managed using a SPECT V/Q-based diagnostic strategy. Among patients with clinically suspected acute PE requiring chest imaging, a SPECT V/Q-based algorithm might be a reliable alternative in clinical practice.