Resistant hypertension and renal denervation

This page starts where routine treatment stops working: the patient on three drugs whose clinic BP will not come down.^[1] How hypertension is diagnosed and staged is covered in Hypertension: diagnosis and staging, and acutely raised BP with organ injury in Hypertensive emergency.

What resistant hypertension is

Picture a patient already taking a RAS blocker, a CCB and a thiazide whose office BP is still high. Before anyone calls that resistant hypertension, both guidelines ask two questions: is the regimen really optimal, and is the high reading real?^[1][2]

ESC 2024 notes that societies use the terms "drug-resistant hypertension", "treatment-resistant hypertension" or "resistant hypertension", which has been reported in 10%–20% of patients with hypertension.^[1] ESC 2024 also says resistant hypertension is not a disease per se.^[1]

Two definitions side by side

^{[1] [2]}

The table shows the main exam trap.^[1][2] AHA/ACC 2025 counts BP at goal on 4 or more drugs as resistant.^[2] ESC 2024 does not use the terms "controlled resistant hypertension" (BP at target but requiring ≥4 medications) or "refractory hypertension" (BP not at target despite ≥5 medications).^[1]

ESC 2024 restates the definition in its section on specific patient groups: BP above goal despite three or more BP-lowering drugs of different classes at maximally tolerated doses, one of them a diuretic.^[1] It says resistant hypertension should be managed at specialised centres able to exclude pseudo-resistant hypertension (adherence testing) and causes of secondary hypertension.^[1]

^[1]

How common it is and why it matters

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ESC 2024 compares patients with resistant hypertension, by any definition, with treated patients who achieve BP control.^[1] Their risk of myocardial infarction (MI), stroke, end-stage renal disease and death may be two- to six-fold higher.^[1] AHA/ACC 2025 puts their risk of MI, stroke, end-stage kidney disease and cardiovascular death at least 50% higher than in hypertension without resistance to treatment.^[2]

• Risk factors (AHA/ACC 2025): multiple cohort studies have identified common risk factors for resistant hypertension, including older age, obesity, chronic kidney disease (CKD) and diabetes.^[2]
• Black populations (AHA/ACC 2025): resistant hypertension is more common, which may be related to adverse social factors, including living in a professional shortage area or disadvantaged neighbourhood, and clinical inertia.^[2]
• Secondary causes (ESC 2024): these are more likely when hypertension is resistant.^[1]
• Obstructive sleep apnoea (ESC 2024): studies indicate that up to 60% of patients with resistant hypertension have features of obstructive sleep apnoea syndrome (OSAS).^[1]
• Non-adherence (AHA/ACC 2025): studies have documented that up to 50% of patients do not adhere to their antihypertensive medications after 1 year of treatment.^[2]

Salt, aldosterone and the sympathetic nervous system

ESC 2024 ties salt and water retention to resistance to treatment; its statement on sympathetic overactivity concerns hypertension in general.^[1]

ESC 2024 says every definition of resistant hypertension requires a diuretic in the regimen.^[1] The reason: excess salt intake and salt and water retention are key players in resistance to BP-lowering treatment.^[1] ESC 2024 adds that resistant hypertension often, and especially in CKD, represents salt retention and volume expansion secondary to relative aldosterone excess.^[1] So BP control may be improved by switching hydrochlorothiazide to a long-acting thiazide-like diuretic such as chlorthalidone.^[1]

Now the aldosterone side. AHA/ACC 2025 defines primary aldosteronism as aldosterone production inappropriately high for sodium and volume status.^[2] That production is relatively autonomous of angiotensin II and potassium, and cannot be completely suppressed with sodium loading.^[2] The excess aldosterone induces intravascular volume expansion, suppressed plasma renin activity, sodium retention, increased potassium excretion, hypertension and cardiovascular and kidney damage.^[2]

The sympathetic side is the target of renal denervation.^[1] ESC 2024 says sympathetic nervous system overactivity contributes to the development and progression of hypertension.^[1] RDN aims to interrupt afferent and efferent sympathetic nerves in the adventitia and perivascular tissue of the renal arteries.^[1]

Renovascular disease works through the renin system.^[1] ESC 2024 defines it as renal artery occlusion or stenosis that lowers renal perfusion pressure enough to activate the renin–angiotensin–aldosterone system (RAAS), raising BP.^[1]

^{[2] [1]}

Confirming true resistance

Most patients who look resistant in clinic are not.^[1] ESC 2024 says most apparent treatment-resistant hypertension is accounted for by non-adherence.^[1] Excluding pseudo-resistance is a prerequisite, and poor adherence should first be checked by careful questioning of the patient; white-coat hypertension must also be excluded.^[1]

Conditions found to cause pseudo-resistance or resistance to BP-lowering treatment (ESC 2024, Table 11)

^[1]

Is the reading real? Out-of-office BP

AHA/ACC 2025 lists what pseudoresistance includes: inaccurate BP measurement, interfering medications, white-coat hypertension and medication nonadherence.^[2] It says white-coat hypertension is excluded with out-of-office BP monitoring.^[2] In apparent treatment-resistant hypertension on office BP, excluding white-coat effect, a form of pseudoresistance, with out-of-office monitoring is reasonable (COR 2a, LOE C-LD).^[2]

Why bother?^[2] AHA/ACC 2025 says evidence suggests that, among individuals with apparent resistant hypertension, higher out-of-office BP is associated with an increased risk of CVD events, independent of office BP.^[2] Home BP and 24-hour ambulatory BP monitoring (ABPM) both predict cardiovascular events better than office BP.^[2] AHA/ACC 2025 prefers home BP monitoring (HBPM) to exclude a white-coat effect in people on treatment, because ABPM is harder to repeat in practice.^[2]

Out-of-office thresholds (ESC 2024 Table 5; AHA/ACC 2025 Table 7)

^{[1] [2]}

ESC 2024 attaches a footnote to the office column of Table 5: its thresholds assume a standardised approach to office BP measurement.^[1] It adds that evidence indicates routine office measurement is often not standardised, and the routine office value may then be 5–10 mmHg higher than a reading taken with the recommended standardised approach.^[1]

ESC 2024 defines white-coat hypertension as BP above the diagnostic threshold in the office but below it at home or on ambulatory monitoring.^[1] Its example: ≥140/90 mmHg in the office but <135/85 mmHg at home or ambulatory daytime (or 24-h BP <130/80 mmHg).^[1]

Is the patient taking the tablets?

ESC 2024 defines adherence as how far a patient's behaviour, such as taking medication, coincides with agreed recommendations from a healthcare provider.^[1] Persistence is the time from initiation to discontinuation of therapy.^[1] Adherence is especially suboptimal in asymptomatic conditions such as hypertension.^[1]

ESC 2024 Figure 11 is titled "Definitions, assessments, and potential interventions for the three phases of adherence to BP-lowering medications".^[1] AHA/ACC 2025 names the 3 phases: initiation; persistence or implementation, consistent with medication taking; and avoiding permanent discontinuation.^[2]

• Once nonadherence is found (AHA/ACC 2025): work with the patient to identify barriers in a nonjudgmental manner, and agree a plan that includes patient preferences and shared decision-making.^[2]
• Mental health (AHA/ACC 2025): screen patients with identified nonadherence for stress, anxiety and depression with valid and reliable scales, with referral for appropriate interventions.^[2]

Improving adherence (AHA/ACC 2025, Section 5.2.5)

^[2]

ESC 2024 lists what to look for at medication review to keep the regimen optimal:^[1]

• drug-related adverse events and appropriate dosing levels;^[1]
• long-acting drugs that require once-daily dosing, and avoiding complex dosing schedules;^[1]
• single-pill combinations whenever feasible;^[1]
• the patient's financial capacity to pay for the regimen in the longer term, if relevant;^[1]
• support from a family member or other social support.^[1]

What else could it be

Think of the differential as three buckets: the reading is wrong, the treatment is wrong, or there is a cause you have not found.^[1]

^{[1] [2]}

About 20% of adults with hypertension report regular use of over-the-counter or nonprescription medications that may raise BP or interfere with treatment, such as NSAIDs or nasal decongestants (AHA/ACC 2025).^[2] These should be reviewed when evaluating resistant hypertension.^[2] Prescription drugs known to raise BP should be replaced with alternatives if possible.^[2] In some settings, such as treating malignant disease, the contributing drug should be continued if hypertension can be controlled.^[2]

Medications and substances that may raise BP (AHA/ACC 2025, Table 11, selected rows)

^[2]

Screening for secondary causes

Once the reading and the regimen are trusted, look for a cause.^[2][1] AHA/ACC 2025: in resistant hypertension, a more detailed evaluation for secondary causes is beneficial for lowering BP and simplifying treatment (COR 1, LOE B-NR).^[2] That evaluation includes careful review of all medications and removal of those with interfering effects on BP.^[2] Secondary hypertension is more common in resistant hypertension, particularly primary aldosteronism, obstructive sleep apnoea (OSA), renal parenchymal disease and renovascular disease.^[2]

ESC 2024 says general practitioners, as gatekeepers to specialist care in most health systems, should be involved in screening for common causes of secondary hypertension, especially sleep apnoea and primary aldosteronism.^[1]

Screening rows (ESC 2024 Recommendation Table 13; AHA/ACC 2025 Section 3.2.3)

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ESC 2024 Table 13 (Optional tests that should be used to screen for secondary hypertension in the presence of suggestive signs, symptoms, or medical history) gives the screening tests by cause.^[1]

Screening tests for secondary hypertension (ESC 2024, Table 13)

^[1]

AHA/ACC 2025 Table 10 (Causes of Secondary Hypertension With Indications for Additional Testing and Diagnostic Screening Tests) names resistant hypertension as an indication for testing for several causes.^[2]

Causes for which AHA/ACC 2025 Table 10 lists resistant hypertension as an indication for testing

^{[2] [2] [1]}

Primary aldosteronism

Normal potassium does not exclude it.^[2][1] AHA/ACC 2025 says spontaneous hypokalaemia is present in only 20% to 50% of patients with primary aldosteronism.^[2] So the decision to screen should not rely on a history of hypokalaemia alone.^[2] ESC 2024 agrees: hypokalaemia is strongly suggestive, but most patients diagnosed with primary aldosteronism have no history of it, so the ARR is recommended for screening.^[1]

• Who to screen (AHA/ACC 2025, COR 1, LOE C-EO): adults with hypertension and any of resistant hypertension (regardless of whether hypokalaemia is present), hypokalaemia (spontaneous or diuretic induced), OSA, incidentally discovered adrenal mass, family history of early-onset hypertension, or stroke at a young age (<40 years).^[2]
• Which test (AHA/ACC 2025, COR 1, LOE C-LD): plasma aldosterone, renin activity and the plasma aldosterone to renin activity ratio for initial screening.^[2]
• Interpreting it (AHA/ACC 2025): renin activity is typically suppressed (<1 ng/mL/h); most data support a plasma aldosterone of at least 10 ng/dL to call the test positive, but additional evaluation may be indicated if renin activity is suppressed; the most commonly used ARR cut-off is 30 with aldosterone in ng/dL and renin activity in ng/mL/h, although some data support 20 or 40.^[2]
• Preparing the patient (AHA/ACC 2025): unrestricted salt intake, serum potassium in the normal range (to avoid false-negative testing) and, ideally, MRA withdrawn for at least 4 weeks before testing.^[2]
• Other drugs (AHA/ACC 2025, COR 1, LOE C-EO): continue most antihypertensive medications, other than MRAs, before initial screening to minimise barriers to or delays in screening.^[2]
• Repeat testing (AHA/ACC 2025): if results are negative or borderline with high suspicion and confirmation would change management, interfering drugs may be temporarily swapped for non-interfering ones (non-dihydropyridine CCBs, vasodilators, peripheral alpha-blockers and potentially dihydropyridine CCBs) for at least 2 to 4 weeks before repeat testing.^[2]
• Referral (AHA/ACC 2025, COR 1, LOE C-EO): a positive screen, or continued suspicion based on suppressed plasma renin or disproportionate target organ damage, should prompt referral to a hypertension specialist or endocrinologist.^[2]

ESC 2024 describes two approaches in patients already on treatment.^[1]

• Test on current drugs: keep baseline BP-lowering drugs unchanged and interpret the ARR in the context of the specific medications taken.^[1]
• "Clean" screen: stop drugs that affect renin and aldosterone whenever feasible; these include beta-blockers, centrally acting drugs (eg, clonidine and alpha-methyldopa), RAS blockers and diuretics.^[1]
• Substitutes: long-acting CCBs (dihydropyridine or non-dihydropyridine) and alpha-receptor antagonists do not interfere with the ARR; if these are contraindicated or insufficient, centrally acting sympatholytics can be used, at the risk of slightly more false positives (by renin suppression).^[1]
• MRAs that cannot be stopped: when MRAs cannot be stopped for safety reasons (severe hypokalaemia or severe hypertension in patients with severe hyperaldosteronism), recent evidence suggests ARR accuracy on the MRA is only marginally affected, particularly in florid primary aldosteronism.^[1]

Drugs and conditions that affect aldosterone, renin, and aldosterone-to-renin ratio (ESC 2024, Table 12, selected rows)

^[1]

ESC 2024 says sodium intake (preferably 24 h urinary sodium, or the morning urine sodium-to-creatinine ratio) matters when interpreting the ARR.^[1] So does the time in the menstrual cycle in women, and ARR cut-offs vary with the unit of measurement and the local laboratory.^[1]

Sleep apnoea, renovascular disease and phaeochromocytoma

• OSAS (ESC 2024): it should be suspected in patients with hypertension and suggestive symptoms, in all patients with resistant hypertension, and in patients with a non-dipping or reverse-dipping pattern on 24 h monitoring, especially if obese.^[1]
• OSAS diagnosis (ESC 2024): lack of suggestive symptoms does not rule it out; a simplified polysomnogram confirms the diagnosis (apnoea–hypopnoea index, AHI, above 5) and grades severity as mild (AHI below 15), moderate (15–30) or severe (above 30).^[1]
• Renovascular hypertension (ESC 2024): very elevated renin levels raise suspicion, though not highly sensitive; work-up uses imaging such as renal artery Doppler ultrasound with bilateral assessment of renal arterial resistive index, or abdominal CT angiography or MRI.^[1]
• Bystander stenosis (ESC 2024): renal artery stenosis may be present in essential hypertension without causing secondary hypertension due to renovascular hypertension.^[1]
• Phaeochromocytoma/paraganglioma (ESC 2024): suspect it with signs and symptoms of catecholamine excess, in syndromic disease, with a family history and in carriers of a germline mutation in a causative gene; normetanephrine and metanephrine are preferred as screening tests because they are secreted constitutively.^[1]

Drug treatment, step by step

Both guidelines name an aldosterone antagonist as the fourth drug: spironolactone in ESC 2024, an MRA in AHA/ACC 2025.^[1][2] Before adding it, make sure the first three are the right three, at the right doses, ideally in one pill.^[1][2]

^[1]

ESC 2024 Recommendation Table 30 (Recommendations for treating resistant hypertension) repeats the two steps for resistant hypertension.^[1]

• With BP uncontrolled despite first-line BP-lowering therapies, adding spironolactone to existing treatment should be considered (Class IIa, Level B).^[1]
• If spironolactone is not effective or tolerated, eplerenone instead, or a beta-blocker if not already indicated and, next, a centrally acting drug, an alpha-blocker, hydralazine or a potassium-sparing diuretic should be considered (Class IIa, Level B).^[1]
• Combining two RAS blockers (an ACE inhibitor and an ARB) is not recommended (ESC 2024 Recommendation Table 16, Class III, Level A).^[1]

ESC 2024 also says when to label and refer.^[1] If BP is still uncontrolled on maximally tolerated triple combination (RAS blocker, CCB and diuretic) after adherence is assessed, the patient should be considered resistant and referred to an expert centre.^[1] At the same time, the addition of spironolactone should be considered.^[1]

AHA/ACC 2025 drug rows for resistant hypertension

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Getting the first three right

• Single pill (ESC 2024): the text says BP-lowering treatment of resistant hypertension with single-pill combinations is recommended to reduce the pill burden, thereby increasing drug adherence and persistence (no class or level given); separately, Recommendation Table 16 says that in patients receiving combination BP-lowering treatment, fixed-dose single-pill combination treatment is recommended (Class I, Level B).^[1]
• Diuretic choice (ESC 2024): BP control may be improved by switching hydrochlorothiazide to a long-acting thiazide-like diuretic such as chlorthalidone.^[1]
• The head-to-head trial (ESC 2024): a recent trial of chlorthalidone vs hydrochlorothiazide, which probably included a sizeable proportion of adults with resistant hypertension, showed no difference in systolic BP or CVD outcomes, with a strong trend of benefit for chlorthalidone in the subgroup with prior CVD; hypokalaemia was more frequent with chlorthalidone.^[1]
• Diuretic choice (AHA/ACC 2025): replacing thiazide-type diuretics (eg, HCTZ or bendroflumethiazide) with thiazide-like diuretics (eg, chlorthalidone and indapamide) may offer additional BP reduction and cardiovascular protection among patients with previous MI or stroke.^[2]
• Terminology (AHA/ACC 2025): the guideline says it uses "thiazide-type diuretic" throughout to refer collectively to hydrochlorothiazide, chlorthalidone and indapamide, yet its MRA row names thiazide-like diuretics (chlorthalidone or indapamide), so read each row for the agents it names.^[2]
• Low eGFR (ESC 2024): with eGFR below 30 mL/min/1.73 m², an adequately up-titrated loop diuretic is necessary to define resistant hypertension.^[1]
• Lifestyle (ESC 2024): ESC 2024 reports that the TRIUMPH trial (Treating Resistant Hypertension Using Lifestyle Modification to Promote Health) found significant clinic and ambulatory BP reductions in patients with resistant hypertension taking part in a 4-month lifestyle intervention of diet and exercise delivered within a cardiac rehabilitation programme.^[1]

Spironolactone and other MRAs

MRAs in resistant hypertension

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Why the potassium and eGFR limits?^[1] ESC 2024 says spironolactone, especially added to RAS inhibitors, increases the risk of hyperkalaemia.^[1] Its efficacy and safety for resistant hypertension have not yet been established in significant renal impairment.^[1] Steroidal MRAs are contraindicated with an eGFR below 30 mL/min/1.73 m².^[1] In resistant hypertension with CKD (eGFR 25–45 mL/min/1.73 m²), ESC 2024 reports that the potassium binder patiromer enabled more patients to continue spironolactone.^[1]

ESC 2024 lists the anti-androgenic effects that can limit spironolactone: breast tenderness or gynaecomastia (in about 6%), impotence in men and menstrual irregularities in women.^[1] AHA/ACC 2025 says a nonsteroidal MRA has not been tested in a trial for resistant hypertension with moderate to advanced CKD.^[2] It may be considered in selected patients with close monitoring of serum potassium.^[2]

Why spironolactone is only Class IIa in ESC 2024

ESC 2024 says spironolactone, an MRA, appears to be the most effective drug at further lowering BP in resistant hypertension, but more evidence of CVD risk-lowering effects with MRAs among all hypertensive populations, especially those without resistant hypertension, is needed.^[1] Its task force requires trial evidence of CVD outcome benefit for a Class I drug recommendation, and no MRA outcome trials have been run in general samples of patients with primary hypertension.^[1] So MRAs received Class IIa, although the 2018 ESC/ESH guideline gave spironolactone Class I.^[1] ESC 2024 calls its Class IIa row an endorsement of MRAs for resistant hypertension that acknowledges some uncertainty about outcome benefit.^[1]

When an MRA cannot be used

• Beta-blockers (ESC 2024): when not already prescribed for a compelling indication, they should be considered, though their BP-lowering effect appears less potent than spironolactone in resistant hypertension.^[1]
• Amiloride and clonidine (ESC 2024): data suggest they are as effective as spironolactone for BP lowering, though they lack outcomes data.^[1]
• Amiloride (AHA/ACC 2025): when spironolactone or eplerenone are not tolerated because of side effects or cost, amiloride (10-20 mg) has been shown to be as effective as spironolactone in adults with resistant hypertension.^[2]
• Head-to-head (AHA/ACC 2025): the BP reduction with spironolactone was greater than with added doxazosin or bisoprolol, and greater than with clonidine in a separate clinical trial.^[2]
• Other options (ESC 2024): a non-exhaustive list of medications sometimes used includes other centrally acting drugs (eg, methyldopa), hydralazine, aliskiren, minoxidil, triamterene and loop diuretics; minoxidil use is often limited by side effects.^[1]
• Fourth- and fifth-line (AHA/ACC 2025): alternatives include beta-blockers, alpha-blockers, central sympatholytic drugs and direct vasodilators; direct vasodilators such as hydralazine and minoxidil should be used with a beta-blocker and a loop diuretic, given their effects on sympathetic tone, sodium reabsorption and fluid retention.^[2]
• Aprocitentan (AHA/ACC 2025): a dual endothelin A and B receptor antagonist that reduced 24-hour ambulatory SBP by 4 to 6 mm Hg vs placebo in adults with resistant hypertension when added to a CCB, RAS inhibitor and HCTZ; it has not been compared directly with spironolactone, and in the PRECISION trial oedema/fluid retention occurred in 9% at 12.5 mg (the FDA-approved dose), 18% at 25 mg (unapproved) and 2% with placebo.^[2]

ESC 2024 says newer agents, such as the non-steroidal MRA finerenone and the aldosterone synthase inhibitor baxdrostat, which lower BP in resistant hypertension, are also being tested for treating primary aldosteronism.^[1] Among its gaps in evidence, ESC 2024 lists CVD outcomes-based data on MRAs as add-on therapy solely for resistant hypertension.^[1]

Renal denervation and other devices

ESC 2024 says that, of the devices investigated for treating resistant hypertension, the most evidence is available for catheter-based RDN; its own rows and the AHA/ACC 2025 rows follow, each with its conditions.^[1] ESC 2024 recalls that the 2018 ESC/ESH guideline did not recommend device-based therapy for routine treatment outside clinical studies and RCTs.^[1] That position rested on negative data with first-generation radiofrequency catheters.^[1] Later sham-controlled trials of second-generation radiofrequency and ultrasound catheters showed BP lowering in a broad range of patients, with and without BP-lowering drugs, including resistant hypertension.^[1]

ESC 2024 renal denervation rows

^[1]

ESC 2024 Recommendation Table 30 carries the resistant-hypertension row again (Class IIb, Level B).^[1] Its wording: to reduce BP, and if performed at a medium-to-high volume centre, catheter-based RDN may be considered for resistant hypertension uncontrolled despite a three-drug combination.^[1] The patient must express a preference after a shared risk-benefit discussion and multidisciplinary assessment.^[1]

AHA/ACC 2025 renal denervation rows

^[2]

Who is a candidate (AHA/ACC 2025, Table 25)

^{[2] [2] [1]}

How much does it lower BP?

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ESC 2024 says the average effect appears no more than one standard BP-lowering medication.^[1] So many adults undergoing RDN will likely need ongoing BP-lowering drugs after the procedure.^[1] AHA/ACC 2025 says that on a 2- to 5-agent regimen or with resistant hypertension, newer-generation devices appear variable.^[2] Some trials showed a small but significant 3 to 5 mm Hg fall in 24-hour ambulatory SBP over sham; others failed to reach their primary endpoint.^[2] In resistant hypertension, the SBP fall with RDN was inferior or similar to adding spironolactone as the fourth agent in 2 RCTs.^[2] But 10% to 40% of patients in those trials could not tolerate spironolactone.^[2]

Durability: ESC 2024 cites long-term, non-randomised follow-up data from the Global Symplicity Registry and three trials (Symplicity HTN-3, the Spyral HTN-ON MED pilot and RADIANCE-HTN SOLO).^[1] These indicate a sustained BP-lowering effect for up to 3 years.^[1] The effect might be "always on", which makes RDN attractive for patients with suboptimal medication adherence.^[1]

Why ESC 2024 holds back

AHA/ACC 2025 says RDN should not be considered a curative therapy or a full replacement for antihypertensive drugs.^[2] Its reasons are short follow-up, modest BP-lowering effects and the absence of CVD outcome trials.^[2] It says RDN should be reserved for adults who develop intolerable side effects to optimal antihypertensive regimens.^[2]

Selecting and preparing the patient

• Team (ESC 2024): a multidisciplinary hypertension team, including experts in hypertension and percutaneous cardiovascular interventions, is recommended to evaluate the indication and perform the procedure.^[1]
• Shared decision (ESC 2024): patients must be fully informed about the benefits, limitations and risks of RDN.^[1]
• Who sees the patient (AHA/ACC 2025): a hypertension specialist with expertise in screening for secondary hypertension or conditions in which RDN is inappropriate, and an interventionalist trained in the procedure and its complications.^[2]
• Work-up (AHA/ACC 2025): directly treatable secondary hypertension, white-coat hypertension and supine hypertension with orthostatic hypotension were exclusion criteria in most trials, so evaluation should include 24-hour ambulatory BP and orthostatic vital signs as well as screening for secondary hypertension.^[2]
• Trial populations (AHA/ACC 2025): almost all trials enrolled only patients with raised systolic and diastolic BP and an eGFR of at least 40 mL/min/1.73 m²; benefit in isolated systolic hypertension or advanced CKD remains uncertain.^[2]
• Anatomy (AHA/ACC 2025): trials included only renal artery diameters between 3 and 8 mm and excluded pre-existing renal artery abnormalities such as fibromuscular dysplasia, renal artery stenosis, renal stent and renal artery aneurysm; renal artery disease (stenosis, dissection, renal stenting) is considered a contraindication.^[2]
• Response (AHA/ACC 2025): predictors of BP response have not been consistently demonstrated among clinical trials.^[2]

Other devices

ESC 2024 says most other device therapies aim to modulate autonomic nervous system activity (baroreflex activation therapy, endovascular baroreflex amplification therapy and carotid body ablation).^[1] These device-based therapies are not recommended for routinely treating hypertension until further evidence on their safety and efficacy becomes available.^[1]

Specific scenarios

Chronic kidney disease

• Definition (ESC 2024): with eGFR below 30 mL/min/1.73 m², an adequately up-titrated loop diuretic is necessary to define resistant hypertension.^[1]
• Spironolactone (ESC 2024): restrict to eGFR ≥30 mL/min/1.73 m² and potassium ≤4.5 mmol/L; steroidal MRAs are contraindicated below eGFR 30 mL/min/1.73 m².^[1]
• MRA row (AHA/ACC 2025): the COR 1 row (adding an MRA in adults with uncontrolled resistant hypertension despite optimal ACEi or ARB, CCB and thiazide-like diuretic) requires an eGFR of ≥45 mL/min/1.73 m².^[2]
• Potassium binder (ESC 2024): in resistant hypertension with CKD (eGFR 25–45 mL/min/1.73 m²), patiromer enabled more patients to continue spironolactone.^[1]
• RDN (ESC 2024): not recommended for treating hypertension in patients with moderate-to-severely impaired renal function (eGFR <40 mL/min/1.73 m²) or secondary causes of hypertension, until further evidence becomes available (Class III, Level C); ESC 2024 notes that sham-controlled trials to date excluded patients with severely reduced kidney function at baseline.^[1]
• RDN (AHA/ACC 2025): the COR 2b row requires an eGFR of ≥40 mL/min/1.73 m².^[2]
• Stage 4 CKD (ESC 2024): chlorthalidone, typically added to a loop diuretic, also effectively lowers BP and reduces microalbuminuria in resistant hypertension with stage 4 CKD (eGFR 15–30 mL/min/1.73 m²).^[1]

The ESC 2026 cardiovascular disease and CKD guideline (PMID 42661426), published on 28 August 2026, is not held as text for this topic (version of record unreachable). None of its rows are used, and the ESC rows in this subsection are from the 2024 ESC hypertension guideline.^[1]

Primary aldosteronism confirmed

• Most common form (ESC 2024): primary aldosteronism (Conn syndrome) is the most common form of secondary hypertension; unilateral forms are amenable to surgery, while bilateral forms need lifelong medical treatment.^[1]
• Lateralising (ESC 2024): in sporadic forms, adrenal vein sampling or functional imaging with radiolabelled tracers distinguishes unilateral from bilateral disease.^[1]
• Unilateral disease (ESC 2024): surgical removal of the adrenal gland is typically considered unless the patient is older or has comorbidities of concern.^[1]
• Bilateral disease (ESC 2024): surgery is not an option and medical treatment is currently based on MRAs; the effective spironolactone dose, usually 50–100 mg once daily, can be titrated up to 300–400 mg once daily if necessary.^[1]
• Eplerenone (ESC 2024): less potent and needs twice-daily dosing, but causes less gynaecomastia and erectile dysfunction in men.^[1]
• Confirmation and lateralisation (AHA/ACC 2025): an aldosterone suppression test, such as an IV saline suppression test or oral salt-loading test, may be needed; if the patient wants surgery, adrenal venous sampling decides between unilateral laparoscopic adrenalectomy and MRA treatment.^[2]
• Subtypes (AHA/ACC 2025): bilateral adrenal hyperplasia in two-thirds; unilateral production in about one-third (aldosterone-producing adenoma, less commonly unilateral hyperplasia or, rarely, adrenal carcinoma).^[2]
• Risk (AHA/ACC 2025): meta-analyses of matched studies showed 2.0-fold risk of heart failure, 2.8-fold of stroke, 1.7-fold of coronary artery disease, 4.0-fold of AF and more kidney damage than primary hypertension.^[2]

Obstructive sleep apnoea

• CPAP row (AHA/ACC 2025): in adults with resistant hypertension and moderate-to-severe OSA, CPAP treatment can be useful in reducing BP (COR 2a, LOE B-R).^[2]
• Size of effect (AHA/ACC 2025): several RCTs showed short-term CPAP can reduce high office and ambulatory BP by 2 to 5 mm Hg, including in resistant hypertension.^[2]
• HIPARCO-2 (AHA/ACC 2025 reports): in patients with OSA and resistant hypertension followed for 59 months, those adherent to CPAP (≥4 hours/night) had significant falls in mean 24-hour ABPM, including night-time SBP and DBP (−5.5 and −4.9 mm Hg), compared with non-adherent CPAP users.^[2]
• By severity (ESC 2024): CPAP is indicated for moderate (AHI 15–30) and severe (AHI above 30) OSAS and usually improves BP control and helps resolve resistant hypertension; for mild OSAS (AHI below 15), weight loss and sleep hygiene advice are usually sufficient.^[1]

Renovascular hypertension

Renovascular rows (ESC 2024 hypertension guideline Recommendation Table 31; AHA/ACC 2025 Section 3.2.3.2)

^{[1] [2]}

The ESC 2024 guideline on peripheral arterial and aortic diseases has its own renal artery rows.^[6] They are worded differently from the hypertension guideline rows above, so state each with its source.^[6][1]

Renal artery disease rows (ESC 2024 peripheral arterial and aortic diseases guideline: every row of Recommendation Table 31, plus its Recommendation Table 30 row on high-risk features and kidney viability)

^[6]

The two ESC 2024 documents class open surgical revascularisation differently.^[1][6] The hypertension guideline says that, with an indication for renal artery revascularisation and technically unfeasible or failed angioplasty and stenting, open surgical revascularisation may be considered (Class IIb, Level C).^[1] The peripheral arterial and aortic diseases guideline says that, with an indication for renal artery revascularisation and complex anatomy, or after failed endovascular revascularisation, open surgical revascularisation should be considered (Class IIa, Level B).^[6]

ESC 2024 says patients with renovascular hypertension should receive medical therapy to reduce BP in the first instance.^[1] It names percutaneous transluminal renal angioplasty (PTRA) without stenting as the treatment of choice for fibromuscular dysplasia, which can restore renal perfusion pressure and lower BP.^[1] When PTRA for fibromuscular dysplasia is not feasible, RAS blockers are the drugs of choice, but they need careful monitoring of renal function over time.^[1] They can cause acute renal failure in those with tight bilateral stenoses or a stenosed solitary functioning kidney.^[1] AHA/ACC 2025 says angioplasty alone without stenting can improve and even normalise BP in non-atherosclerotic disease, especially with recent-onset or resistant hypertension.^[2]

Diabetes and drug-induced hypertension

ESC 2024 reports that in resistant hypertension with type 2 diabetes, spironolactone (25–50 mg daily) reduced BP and albuminuria.^[1] Over-the-counter medications, prescribed drugs and drug abuse (recreational substances and misuse of drugs) can cause hypertension (ESC 2024).^[1] BP rises in 80%–90% of patients treated with vascular endothelial growth factor inhibitors.^[1]

Complications and pitfalls

Procedural risk of RDN (ESC 2024): no procedure-related serious safety signals have been reported in first- and second-generation trials beyond the usual risk of femoral arterial access, though most trials were not powered for safety outcomes.^[1] After RDN there is a 0.25%–0.5% rate of renal artery stenosis or dissection requiring stenting.^[1] AHA/ACC 2025 estimates the risk of renal artery stenosis needing intervention at about 0.2% per year, highest in the first 6 months.^[2] It suggests surveillance for renal artery stenosis or dissection with non-invasive imaging (eg, duplex Doppler, CT angiogram or magnetic resonance angiography) after RDN.^[2] RDN is currently performed strictly via the femoral artery, with immediate risk not significantly greater than femoral access alone.^[2]

Renovascular disease neglected: ESC 2024 says some null trials, which did not solely recruit patients with true significant atherosclerotic renovascular hypertension, have decreased enthusiasm for investigating atherosclerotic renal artery stenosis.^[1] This could result in more uncontrolled hypertension, recurrent flash pulmonary oedema (Pickering syndrome) and worsening renal function ultimately leading to end-stage renal disease.^[1]

Prognosis, referral and follow-up

Referral is a formal ESC 2024 row (Recommendation Table 12, Recommendations for resistant hypertension work-up).^[1] Patients with resistant hypertension should be considered for referral to clinical centres with expertise in hypertension management for further testing (Class IIa, Level B).^[1] ESC 2024 explains that the work-up is complex and often requires technologies not available to general practitioners.^[1]

• After a positive screen (AHA/ACC 2025, COR 2a, LOE C-EO): referral to a clinician with expertise in that form of secondary hypertension is reasonable.^[2]
• Rarer secondary forms (ESC 2024): other forms of secondary hypertension, such as genetic causes (Liddle's syndrome, glucocorticoid-remediable aldosteronism), excess liquorice, Cushing's syndrome, thyroid disease, hyperparathyroidism, aortic coarctation and acromegaly, are rare, and affected patients should be referred to specialised centres for treatment.^[1]
• Electrolytes on an MRA (ESC 2024): monitor serum electrolytes and kidney function soon after starting and frequently thereafter.^[1]
• After RDN (AHA/ACC 2025): because of the risk of renal artery stenosis after the procedure, patients will require ongoing surveillance imaging.^[2]

Special populations

• Pregnancy (AHA/ACC 2025): pregnancy is listed as a contraindication to RDN (Table 25).^[2]
• Pregnancy and familial hyperaldosteronism (ESC 2024): of the familial forms, only glucocorticoid-remediable primary aldosteronism (familial hyperaldosteronism type 1) can be corrected with dexamethasone, usually at low doses free of glucocorticoid effects that can be used safely during pregnancy.^[1]
• Younger women and children (ESC 2024): fibromuscular dysplasia may cause renovascular hypertension, especially in children and younger women.^[1]
• Older adults (ESC 2024): atherosclerosis is the most common form of renovascular hypertension, especially in older adults.^[1]
• Black adults (AHA/ACC 2025): resistant hypertension is more common in Black populations.^[2]
• Women on oral contraceptives (AHA/ACC 2025 Table 11): avoid use in women with uncontrolled hypertension.^[2]
• Young women (ESC 2024): combined oestrogen-progesterone contraceptives are among the most common causes of drug-induced hypertension in young women and should not be used in hypertensive women unless no other method is available or acceptable to the patient.^[1]

Evidence, guidelines and regional differences

^{[1] [2]}

ESC 2024 lists cardiovascular outcomes trials of RDN among its gaps in evidence.^[1] AHA/ACC 2025 notes that broader indications are approved for RDN devices by the US Food and Drug Administration (FDA).^[2]

In Australia and New Zealand

The guidance in this subsection is Australian. The National Heart Foundation of Australia guideline for the diagnosis and management of hypertension in adults (2016) is quoted here from its PubMed summary abstract.^[3]

• Target (NHFA 2016): treat uncomplicated hypertension to a target BP of <140/90 mmHg or lower if tolerated.^[3]
• Out-of-clinic BP (NHFA 2016): ambulatory and/or home BP monitoring should be offered if clinic BP is ≥140/90 mmHg, as out-of-clinic BP is a stronger predictor of outcome.^[3]
• Measurement (Hypertension Australia and National Hypertension Taskforce of Australia position statement): automated office BP (AOBP) is the recommended measurement standard; its average is comparable to the 24-h ambulatory daytime mean, and the AOBP hypertension threshold is 135/85 mmHg.^[4]
• Control (National Hypertension Taskforce of Australia): the crude BP control rate improved to 39.6% in 2022-2023 on National Health Survey data, with methodology changes to consider; younger people and those in socioeconomically disadvantaged areas have substantially lower control, against a goal of 70% control by 2030.^[5]

No Australian or New Zealand guideline on resistant hypertension or renal denervation was found in the census for this topic (PubMed, 2026-10-09). So the drug sequence and RDN rows above are the ESC 2024 and AHA/ACC 2025 rows.^[1][2]

Guidelines checked for this topic

Rows on this page come from the 2024 ESC hypertension guideline and the 2025 AHA/ACC high blood pressure guideline, plus the renal artery rows of the 2024 ESC peripheral arterial and aortic diseases guideline and the Australian sources named above.^{[1][2][6][3][4][5]} The two hypertension guidelines are the newest ESC and AHA/ACC hypertension guidelines among the guidelines checked for this topic (census 2026-10-09). A 2026 ACC Expert Consensus Decision Pathway on resistant hypertension was published on 5 October 2026; it is not held as text for this topic and is not used. The 2026 ESC Guidelines for the management of cardiovascular disease and chronic kidney disease (PMID 42661426) were published on 28 August 2026; they are not held as text for this topic and are not used (see Chronic kidney disease, above). The 2026 AHA/ACC/ADA/ASN guideline on cardiovascular-kidney-metabolic syndrome (JACC, PMID 42265997) is among the guidelines checked for this topic: it has no resistant-hypertension, renal denervation or primary aldosteronism rows, and it mentions treatment-resistant hypertension only in a list of groups for sleep apnoea screening.

Exam pearls

• ESC 2024 resistant hypertension: office systolic and diastolic BP not lowered to below 140 mmHg and/or 90 mmHg despite lifestyle measures and maximum or maximally tolerated doses of a thiazide or thiazide-like diuretic, a RAS blocker and a CCB, confirmed by out-of-office BP.^[1]
• AHA/ACC 2025 adds BP at goal on 4 or more drugs; ESC 2024 does not use "controlled resistant" or "refractory" hypertension.^[2][1]
• Home and daytime ambulatory hypertension threshold: ≥135/85 mmHg; 24-h ABPM ≥130/80 mmHg (ESC 2024 Table 5).^[1]
• Objective adherence testing in apparent resistant hypertension: ESC 2024 Class IIa, Level B, if resources allow.^[1]
• Spironolactone 25–50 mg daily; restrict to eGFR ≥30 mL/min/1.73 m² and potassium ≤4.5 mmol/L (ESC 2024).^[1]
• Amiloride (10-20 mg) has been shown to be as effective as spironolactone in adults with resistant hypertension when spironolactone or eplerenone are not tolerated because of side effects or cost (AHA/ACC 2025).^[2]
• RDN for resistant hypertension: ESC 2024 Class IIb, Level B (BP uncontrolled despite a three-drug combination including a thiazide or thiazide-like diuretic, medium-to-high volume centre, patient preference after shared risk-benefit discussion and multidisciplinary assessment); AHA/ACC 2025 COR 2b, LOE B-R (as an adjunct to BP medications and lifestyle modification in carefully selected patients with office SBP 140-180 and DBP ≥90 mm Hg and eGFR ≥40 mL/min/1.73 m², with resistant hypertension despite optimal treatment or intolerable side effects to additional drugs); as a first-line BP-lowering intervention, ESC 2024 Class III, Level C.^[1][2]
• Primary aldosteronism: 20% of patients with resistant hypertension (AHA/ACC 2025); screen regardless of potassium (COR 1, LOE B-NR).^[2]

References6ShowHide

1. [1]McEvoy JW, et al. 2024 ESC Guidelines for the management of elevated blood pressure and hypertension. Eur Heart J, 2024.PMID 39210715
2. [2]Jones DW, et al. 2025 AHA/ACC/AANP/AAPA/ABC/ACCP/ACPM/AGS/AMA/ASPC/NMA/PCNA/SGIM Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol, 2025.PMID 40815242
3. [3]Gabb GM, et al. Guideline for the diagnosis and management of hypertension in adults - 2016. Med J Aust, 2016.PMID 27456450
4. [4]Sharman JE, et al. Automated office blood pressure measurement: a Hypertension Australia and National Hypertension Taskforce of Australia position statement. J Hypertens, 2025.PMID 40534535
5. [5]Ohlrogge AH, et al. Update from the National Hypertension Taskforce of Australia: prevalence, treatment and control rates of hypertension between 2022 and 2024 - implications and future directions. J Hypertens, 2026.PMID 42223442
6. [6]Mazzolai L, et al. 2024 ESC Guidelines for the management of peripheral arterial and aortic diseases. Eur Heart J, 2024.PMID 39210722