Beyond Conventional Combination Therapy: Emerging Pharmacological and Device-Based Strategies for Uncontrolled and Resistant Hypertension

<jats:p>Аrterial hypertension (HTN) remains the leading modifiable cardiovascular risk factor worldwide, yet blood pressure (BP) control remains suboptimal in a substantial proportion of treated patients, including those with resistant HTN. This narrative literature review summarizes emerging pharmacological and device-based strategies that extend beyond conventional combination therapy. We critically review the current evidence regarding the clinical benefits of endothelin-receptor antagonists, selective aldosterone-synthase inhibitors, RNA interference targeting hepatic angiotensinogen, and the complementary BP-lowering effects of sacubitril/valsartan, sodium–glucose cotransporter 2 inhibitors, and non-steroidal mineralocorticoid receptor antagonists. We also discuss novel non-pharmacological approaches to the treatment of difficult-to-control HTN, including baroreflex activation therapy, endovascular baroreflex amplification, and other investigational neuromodulatory strategies. Several of these approaches achieve clinically meaningful BP reductions and may target distinct pathophysiological mechanisms or help overcome adherence-related barriers. However, the available evidence remains heterogeneous, and for most emerging antihypertensive therapies, adequately powered trials demonstrating reductions in major cardiovascular events and long-term comparative effectiveness are still lacking. Future management of HTN will likely combine guideline-directed single-pill regimens with phenotype-guided pharmacotherapy and carefully selected device-based interventions.</jats:p>