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CLINICAL STATEMENTS AND GUIDELINES Circulation. 2025;152:e114–e218. DOI: 10.1161/CIR.0000000000001356 September 16, 2025 e177 ence of a 2- to 5-agent antihypertensive drug regimen or resistant hypertension, the efficacy of newer-generation devices appears variable. While some trials showed a small but significant reduction in 24-hour ambulatory SBP by 3 to 5 mm Hg over the sham arm,13,14 others failed to reach their primary endpoint.29–31 Although broader indications are approved for the RDN devices by the FDA, given the relatively short duration of followup in clinical trials with modest BP-lowering effects and the absence of CVD outcome trials, RDN should not be considered as a curative therapy for hypertension or full replacement for antihypertensive drugs. Recommendation-Specific Supportive Text 1 Approximately 20% of adults with hypertension reported regular use of over-the-counter or nonpre scription medications that may directly raise BP or interfere with antihypertensive drug efficacy, such as NSAIDs or nasal decongestants (Table 17).2 These medications are associated with uncontrolled BP and should be reviewed during evaluation of patients with resistant hypertension.2 Some prescription drugs are known to elevate BP and should be replaced with alternative agents that avoid hypertensive side effects, if possible; however, in some settings, such as the treatment of malignant diseases, the contributing medication should be continued if hypertension can be controlled. Secondary hypertension is more com mon among adults with resistant hypertension, partic ularly primary aldosteronism, OSA, renal parenchymal disease, and renovascular disease.1 Screening for secondary hypertension is discussed in Section 3.2.3 (“Secondary Forms of Hypertension”). 2. Antihypertensive drug therapy should start with a combination of an ACEi or ARB, a CCB, and a diuretic.15 Replacing thiazide-type diuretics (eg, HCTZ or bendroflumethiazide) with thiazide-like diuretics (eg, chlorthalidone and indapamide) may offer additional BP reduction32,33 and cardiovascu lar protection among patients with previous MI or stroke. 34 RCTs have shown that addition of spirono lactone (25-50 mg/day) as the fourth drug reduced home and 24-hour SBP by 6.6 to 8.7 mm Hg when compared with placebo in patients with resistant hypertension and eGFR ≥45 mL/min/1.73 m2.6,7 The reduction in BP was greater than with addi tion of doxazosin or bisoprolol.6 The magnitude of reduction in 24-hour systolic and diastolic BP was greater with spironolactone than clonidine in a sepa rate clinical trial.8 Nevertheless, 4% to 40% of adults with resistant hypertension cannot tolerate spirono lactone due to hyperkalemia or antiandrogenic side effects.35–38 Eplerenone, a more selective steroidal MRA that avoids the antiandrogenic side effects but may cause hyperkalemia, is a potential alternative to spironolactone, but RCTs have not demonstrated reduction of home BP or 24-hour BP at doses between 25 and 100 mg daily when compared with placebo, and effective treatment may require higher dosages.39–41 Use of nonsteroidal MRA for treating resistant hypertension in patients with moderate to advanced CKD has not been tested in a clinical trial but may be considered in selected patients with close monitoring of serum potassium. 3. When spironolactone or eplerenone are not tolerated due to side effects or cost, amiloride (10-20 mg) has been shown to be as effective as spironolactone in adults with resistant hypertension.42 Other alterna tive fourth- and fifth-line drug therapies include BBs, alpha blockers, central sympatholytic drugs, and direct vasodilators.6,8,9,11,43 However, direct vaso dilators such as hydralazine and minoxidil should be used in combination with a BB and a loop diuretic given their effects on sympathetic tone, sodium reabsorption, and fluid retention.44 Aprocitentan, a dual endothelin A and B receptor antagonist, was shown to reduce 24-hour ambulatory SBP by 4 to 6 mm Hg compared with placebo in adults with resis tant hypertension when added to a CCB, RAS inhib itor, and HCTZ. Aprocitentan has not been directly compared with spironolactone in the treatment of resistant hypertension and edema/fluid retention occurred in 9% at 12.5 mg (FDA‐approved dose) versus 18% at 25 mg (unapproved dose) and 2% with placebo in the PRECISION (A Research Study to Show the Effect of Aprocitentan in the Treatment of Difficult to Control [Resistant] High Blood Pressure [Hypertension] and Find Out More About its Safety) trial.45 4 Almost all RDN trials included only patients with elevation in both systolic and diastolic BP and eGFR of at least 40 mL/min/1.73 m2.13,14,26–28,46 The benefit of RDN for isolated systolic hyper tension or advanced CKD remains uncertain. In addition, only patients with suitable renal anatomy with artery diameters between 3 and 8 mm were included in the trials, while presence of preexist ing renal artery abnormalities, such as fibromus cular dysplasia, renal artery stenosis, renal stent, and renal artery aneurysm were excluded. Among patients with resistant hypertension, the mag nitude of SBP reduction achieved by RDN was shown to be inferior to or similar to the addition of spironolactone as the fourth agent in 2 RCTs38,47; however, between 10% and 40% of patients in the trials36,38 could not tolerate spironolactone. Given the modest BP-lowering effects of RDN over the sham arm or addition of spironolactone, RDN should be reserved for adults with hyperten sion who develop intolerable side effects to opti mal antihypertensive regimens. Patient selection should be made in the same manner as used in clinical trials to maximize clinical outcomes while minimizing potential complications (Table 25). Downloaded from http://ahajournals.org by on October 7, 2026