Renal denervation beyond resistant hypertension: should drug intolerance redefine eligibility?

Catheter-based renal denervation (RDN) is endorsed by major international guidelines as an adjunct to antihypertensive therapy, yet most regulatory and reimbursement frameworks still restrict its use to true resistant hypertension, usually defined as uncontrolled blood pressure (BP) despite three or more maximally tolerated antihypertensive drugs including a diuretic. This restriction leaves a clinically important population without an effective escalation pathway: patients with uncontrolled, high-risk hypertension who cannot tolerate the multi-class drug regimens required to qualify as resistant. We argue that this exclusion is increasingly difficult to justify. Contemporary sham-controlled trials enrolling patients on no or limited antihypertensive therapy demonstrate modest but reproducible ambulatory BP reductions in precisely the pharmacological context in which drug-intolerant patients are managed and guidelines published since 2023 acknowledge uncontrolled hypertension on fewer drugs or drug intolerance as clinically relevant scenarios for RDN. The device-attributable ambulatory systolic effect converges on 4-6 mmHg, 25-40% of treated patients derive no meaningful BP reduction, no pre-procedural variable reliably identifies responders, and no trial has been powered for cardiovascular outcomes. Drug intolerance also lacks an objective definition and frequently reflects undisclosed non-adherence. We propose a pragmatic referral pathway in which biochemical adherence testing and a documented trial of a low dose single-pill combination are mandatory steps, followed by out-of-office BP confirmation, secondary hypertension screening, anatomical eligibility and multidisciplinary shared decision-making.