The impact of polypharmacy on diagnoses, symptoms, and healthcare utilization in patients with syncope

Background/Aims Polypharmacy, defined as the daily use of five or more medications, increases the risk of iatrogenic syncope, adverse drug interactions, and fall injuries. This study aimed to evaluate the impact of polypharmacy on clinical diagnoses, presenting symptoms, and healthcare utilization profiles in patients evaluated for unexplained syncope. Methods We performed a retrospective cross-sectional analysis of a database of 2,690 patients referred for head-up tilt testing (HUTT) for unexplained syncope at Skåne University Hospital (Malmö, Sweden) between 2008 and 2021. Patients were stratified into a polypharmacy group (≥5 concurrent medications) and a non-polypharmacy group (<5 medications). Diagnoses, including vasovagal syncope (VVS), orthostatic hypotension (OH), postural orthostatic tachycardia syndrome (POTS), and carotid sinus syndrome (CSS), were adjudicated according to 2018 ESC syncope guidelines. Results Polypharmacy was identified in 355 patients (13.2%), who were significantly older than the non-polypharmacy cohort (mean age 69.7 vs. 48.0 years, p<0.001). Diagnostic profiles differed substantially: polypharmacy patients had significantly higher rates of OH (23.7% vs. 7.9%, p<0.001) and CSS (7.3% vs. 3.0%, p<0.001). In contrast, non-polypharmacy patients were more likely to be diagnosed with VVS (45.3% vs. 14.7%, p<0.001) and POTS (5.5% vs. 1.7%, p=0.002). Clinically, polypharmacy was associated with a higher incidence of traumatic falls (69.0% vs. 51.8%, p<0.001), whereas non-polypharmacy patients reported more prodromes and palpitations. Healthcare utilization was significantly elevated in the polypharmacy cohort, demonstrating higher rates of emergency room admissions (55.8% vs. 40.2%, p<0.001), brain CT/MRI imaging (71.0% vs. 54.7%, p<0.001), echocardiograms (70.1% vs. 53.1%, p<0.001), and implantable loop recorders (12.4% vs. 8.9%, p=0.04). Furthermore, within the polypharmacy group, concurrent use of psychoactive drugs was linked to significantly more traumatic falls (74.7% vs. 60.2%, p=0.005) and a higher frequency of syncope episodes. Conclusions Patients in the polypharmacy group had a significantly different clinical presentation of syncope, showing higher levels of orthostatic hypotension, traumatic falls, and heightened healthcare resource utilization. The inclusion of psychoactive medications in polypharmacy regimens further exacerbates fall risk and symptom frequency and may highlight the need for targeted medication reviews and deprescribing strategies in this vulnerable population.