Resistant Hypertension: State of the Art Review

Resistant hypertension, defined as blood pressure above target despite treatment with at least three antihypertensive agents (including a diuretic) or controlled blood pressure requiring four or more medications, affects over 140 million individuals globally and confers increased risks of heart failure, stroke, and chronic kidney disease progression. A considerable proportion of cases represent apparent resistant hypertension, in which pseudo-resistance due to inaccurate blood pressure measurement, medication nonadherence, or white-coat effect has not yet been excluded. Ambulatory and home blood pressure monitoring are therefore central to confirming true resistance and identifying high-risk phenotypes, including nocturnal hypertension and abnormal dipping patterns. Excluding pseudo-resistance and secondary causes remains essential before escalating therapy. Resistant hypertension commonly coexists with obesity, type 2 diabetes, and chronic kidney disease (CKD), and is driven by overlapping mechanisms of aldosterone excess, sodium and water retention, and sympathetic activation. Guideline-directed treatment centers on optimization of lifestyle measures and triple therapy with renin-angiotensin system blockade, a calcium channel blocker, and a thiazide-like diuretic, followed by a mineralocorticoid receptor antagonist as preferred fourth-line agent. In patients with CKD, careful assessment of volume status, diuretic selection, kidney function, and hyperkalemia risk is particularly important. Recent therapeutic advances have expanded options for patients who remain uncontrolled. Newly FDA-approved agents aprocitentan and baxdrostat provide additional pharmacologic options for patients inadequately controlled on existing therapy. Renal denervation offers a separate device-based approach for selected patients, while investigational RNA-based and other neuromodulatory therapies may further broaden future treatment options. Future management is likely to move toward more precise, phenotype-guided treatment integrating ambulatory blood pressure patterns, renin-aldosterone biology, volume status, kidney function, and cardiometabolic comorbidities. Improved diagnostic precision and mechanism-based treatment strategies may reduce persistent treatment gaps and improve long-term cardiovascular and kidney outcomes.