Comparison of trinitroglycerin and adenosine as provocative agents for head-up tilt test in patients with unexplained syncope: a semi-crossover randomized clinical trial with prospective follow-up

Purpose Head-up tilt test (HUTT) is a reasonable diagnostic evaluation for patients with suspected vasovagal syncope; however, its lengthy duration is a remarkable limitation. Although adenosine (AD), as an alternative provocative agent, is a promising option for tackling this shortcoming, it received little appreciation in the literature. We aimed to compare the efficacy and the time to elicit a positive response to HUTT for sublingual trinitroglycerin (TNG) and intravenous AD. Furthermore, we evaluated patients' outcomes in the follow-up. Methods Patients with a chief complaint of transient loss of consciousness (TLOC) were evaluated. We randomized patients with the diagnosis of unexplained syncope after diagnostic evaluations, to undergo TNG-augmented HUTT or AD-augmented HUTT. They were crossed over to receive the other medication in case of negative response to the test. In the follow-up, we evaluated traumatic and non-traumatic TLOCs, hospitalization due to syncope, and death in patients. Results We randomized 132 patients (41.70 +/- 19.37 years, 52.3% female) to receive TNG (n= 66) or AD (n= 66). Respectively, the positivity rate of TNG and AD for the first and the crossover-HUTT was 31.1% and 26.7%, and 20.5% and 26.2% with no statistically significant differences in both tests (P> 0.50). The time to positive response was significantly shorter for AD than TNG (P< 0.001). In the follow-up, re-admission was significantly more prevalent in HUTT-negative patients compared to HUTT-positive patients (P= 0.04). Conclusions We found that diagnostic yield of TNG and AD in HUTT is comparable, while AD acts 4 times faster than TNG in evoking a vasovagal response.