Drug-induced orthostatic hypotension: A systematic review and meta-analysis of randomised controlled trials

Abstract

Background Drug-induced orthostatic hypotension (OH) is common, and its resulting cerebral hypoperfusion is linked to adverse outcomes including falls, strokes, cognitive impairment, and increased mortality. The extent to which specific medications are associated with OH remains unclear. Methods and findings We conducted a systematic review and meta-analysis to evaluate the extent to which specific drug groups are associated with OH. EMBASE, MEDLINE, and Web of Science databases were searched from inception through 23 November 2020. Placebo-controlled randomised controlled trials (RCTs) on any drug reporting on OH as an adverse effect in adults (≥18 years) were eligible. Three authors extracted data on the drug, OH, dose, participant characteristics, and study setting. The revised Cochrane risk-of-bias tool for randomised trials (RoB 2) was used to appraise evidence. Summary odds ratios (ORs) were estimated for OH using fixed effects Mantel–Haenszel statistics. We conducted subgroup analysis on validity of OH measurement, drug dose, risk of bias, age, and comorbidity. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool was used to summarise the certainty of evidence. Of 36,940 citations, 69 eligible RCTs were included in the meta-analysis comprising 27,079 participants. Compared with placebo, beta-blockers and tricyclic antidepressants were associated with increased odds of OH (OR 7.76 [95% CI 2.51, 24.03]; OR 6.30 [95% CI 2.86, 13.91]). Alpha-blockers, antipsychotics, and SGLT-2 inhibitors were associated with up to 2-fold increased odds of OH, compared to placebo. There was no statistically significant difference in odds of OH with vasodilators (CCBs, ACE inhibitors/ARBs, SSRIs), compared to placebo. Limitations of this study are as follows: data limited to placebo-controlled studies, (excluding head-to-head trials), many RCTs excluded older participants; therefore results may be amplified in older patients in the clinical setting. The study protocol is publicly available on PROSPERO (CRD42020168697). Conclusions Medications prescribed for common conditions (including depression, diabetes, and lower urinary tract symptoms) were associated with significantly increased odds of OH. Drugs causing sympathetic inhibition were associated with significantly increased odds of OH, while most vasodilators were associated with small nonsignificant differences in odds of OH, compared to placebo. Drugs targeting multiple parts of the orthostatic blood pressure (BP) reflex pathway (e.g. sympathetic inhibition, vasodilation, cardio-inhibitory effects) may carry cumulative risk, suggesting that individuals with polypharmacy could benefit from postural BP monitoring. Cini Bhanu and colleagues evaluate the extent to which different drug groups are associated with orthostatic hypertension in this systematic review and meta-analysis. Author summary Why was this study done? Orthostatic hypotension (OH) is a common side effect of drugs. It causes a reduction in blood pressure (BP) on standing, which results in reduced cerebral blood flow that is linked to falls, strokes, cognitive impairment, and increased mortality. Over 250 medications are associated with OH. However, there is conflicting evidence on the extent to which different drug groups are associated with OH as a side effect. To our knowledge, there are no systematic reviews providing an overview of which drugs are associated with OH. What did the researchers do and find? We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing a drug to placebo, including 69 trials comprising 27,079 participants, to address the extent to which specific medications are associated with OH. We found that drugs primarily inhibiting sympathetic activity were associated with significantly increased odds of OH, compared to placebo (beta-blockers, TCAs, antipsychotics, alpha-blockers). Drugs primarily causing vasodilation (CCBs, ACE inhibitors/ARBs, SSRIs, SGLT-2 inhibitors) were associated with smaller differences that were not statistically significant, compared to placebo. What do these findings mean? Drugs prescribed widely for common conditions including lower urinary tract symptoms, mental health conditions, pain, and insomnia are associated with significantly increased risk of OH; alternative prescribing, shorter treatment, and postural BP checks should be considered to manage this risk. The relationship between antihypertensives and antidiabetic drugs and OH is more complex. Drugs targeting multiple parts of the BP reflex pathway causing OH may carry cumulative risk, suggesting that individuals with polypharmacy could benefit from routine postural BP monitoring.