What is resistant hypertension?

Blood pressure that remains above target despite three different antihypertensive medicines, including a diuretic, taken at optimal or maximally tolerated doses — or blood pressure that is controlled but requires four or more medicines to achieve it. It affects around one in ten treated hypertensive patients and carries a substantially higher risk of stroke, heart attack, heart failure and kidney disease than controlled hypertension. However, the label should not be applied until four things have been excluded: that the patient is actually taking the medicines, that the raised readings are not simply a white coat effect, that the regimen and doses are genuinely appropriate, and that the measurements themselves are accurate. Most apparent resistance is explained by one of these rather than by true biological resistance.

Why is spironolactone the usual fourth drug?

Because a trial designed specifically to answer that question showed it clearly outperforms the alternatives. PATHWAY-2 compared spironolactone with bisoprolol, doxazosin and placebo as an add-on in patients already on three drugs, and spironolactone reduced blood pressure roughly twice as much as the other active options. The finding changed how resistant hypertension is understood: it indicates that the underlying problem in most cases is retention of sodium and fluid driven by aldosterone, rather than excessive sympathetic activity or high renin. Spironolactone requires monitoring — potassium and kidney function should be checked within one to two weeks of starting and after each increase — and if breast tenderness or enlargement occurs in men, eplerenone or amiloride can be substituted.

What is baxdrostat and why does it matter?

Baxdrostat is an aldosterone synthase inhibitor, approved by the FDA in May 2026 as the first mechanistically new class of blood pressure drug in decades. Existing drugs that target aldosterone, such as spironolactone, block the receptor that aldosterone acts on, which causes aldosterone levels themselves to rise in compensation. Baxdrostat instead blocks the enzyme that makes aldosterone, reducing production at source. In its phase 3 trial it produced clinically meaningful reductions in systolic blood pressure when added to existing treatment in patients whose hypertension was uncontrolled or resistant. The main technical challenge for this class is selectivity: the enzyme that makes aldosterone closely resembles the one that makes cortisol, so avoiding interference with cortisol production is essential. Potassium still requires monitoring.

How do doctors know if someone is taking their tablets?

By measuring, rather than asking or guessing — because studies consistently show that clinicians are little better than chance at judging adherence, and that between a third and a half of patients referred with resistant hypertension are not taking their medicines as prescribed. The reference method is laboratory analysis of urine or blood for the prescribed drugs using mass spectrometry, which shows definitively which medicines are present. Other approaches include supervised dosing in clinic with blood pressure observed afterwards, and reviewing pharmacy refill records. Crucially, the response to finding non-adherence should not be reproach: the reasons are usually side effects, cost, complexity, forgetfulness, depression or genuine doubts about whether the treatment is necessary. Simplifying to once-daily single-pill combinations and discussing the concerns openly is far more effective than adding a fifth drug to a prescription that is not being taken.

Which other conditions should be looked for?

Primary aldosteronism is the most important, because it is common in resistant hypertension — present in around a fifth of cases — potentially curable by surgery when one adrenal gland is responsible, and specifically treatable with spironolactone or eplerenone when both are. Despite this it is screened for in fewer than one in twenty eligible patients. Obstructive sleep apnoea is also very common in this group and frequently unrecognised, particularly in people with obesity, snoring or daytime sleepiness. Other causes include narrowing of the renal arteries, chronic kidney disease, phaeochromocytoma, Cushing syndrome and coarctation of the aorta. Just as important is reviewing what the patient is taking or consuming: anti-inflammatory painkillers are among the commonest and most easily missed causes, along with combined oral contraceptives, steroids, decongestants, some antidepressants, liquorice, excessive alcohol and high dietary salt.

How does GMJ News cover resistant hypertension?

GMJ News covers the definition and the four causes of pseudo-resistance, ambulatory and home monitoring including nocturnal dipping patterns, objective adherence measurement and its clinical response, the PATHWAY-2 evidence for spironolactone, the May 2026 FDA approval of baxdrostat as the first aldosterone synthase inhibitor, primary aldosteronism screening with the aldosterone-to-renin ratio and adrenal vein sampling, obstructive sleep apnoea and other secondary causes, interfering drugs and dietary sodium, renal denervation and the SYMPLICITY to SPYRAL trial trajectory, single-pill combinations and WHO HEARTS, the chronotherapy question after TIME, and hypertensive emergency versus urgency. Relevant to PHIG's cardiovascular, NCD and HEARTS implementation programmes.

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Resistant Hypertension

GMJ News knowledge hub · last reviewed September 2026 · Georgian Medical Journal

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Resistant hypertension — blood pressure remaining above target despite three antihypertensive drugs including a diuretic at optimal doses — affects around 10% of treated hypertensive patients and carries substantially elevated cardiovascular and renal risk, yet the majority of apparent cases are not truly resistant at all: non-adherence, white coat effect, inadequate dosing, high dietary sodium and interfering drugs account for most, which is why confirmation by ambulatory or home monitoring and objective adherence assessment must precede any escalation (WHO). Two developments define the field: the PATHWAY-2 trial established spironolactone as the clear fourth-line agent, confirming that resistant hypertension is predominantly a sodium-retention and aldosterone-driven state; and in May 2026 the FDA approved baxdrostat, the first aldosterone synthase inhibitor and the first mechanistically new class of antihypertensive in decades, targeting aldosterone production directly rather than blocking its receptor — alongside the persistent and serious under-diagnosis of primary aldosteronism, which is present in a substantial minority of resistant cases and is potentially curable.

Key messages

Most apparent resistance is not true resistance — confirm before escalating

Resistant hypertension is defined as blood pressure above target despite three antihypertensive agents including a diuretic at optimal or maximally tolerated doses, or controlled blood pressure requiring four or more agents. But the majority of apparent cases are pseudo-resistant. The four causes to exclude first: non-adherence, which is the commonest and is present in 30-50% of apparent resistance when measured objectively; white coat effect, requiring ambulatory or home monitoring to exclude; suboptimal regimen, including inadequate dosing, inappropriate drug combinations or an unsuitable diuretic; and measurement error, including cuff size, arm position and inadequate rest.

Spironolactone is the established fourth-line agent — PATHWAY-2

The PATHWAY-2 trial (Lancet 2015) directly compared spironolactone, bisoprolol, doxazosin and placebo as add-on therapy in resistant hypertension, and spironolactone was clearly superior — reducing home systolic blood pressure roughly twice as much as the other active comparators. The result reframed the pathophysiology: resistant hypertension is predominantly a sodium-retention and aldosterone-driven state rather than a high-renin or sympathetically driven one. Monitoring is essential — potassium and renal function within 1-2 weeks of initiation and after each dose increase — and gynaecomastia may require substitution with eplerenone or amiloride.

Baxdrostat — first aldosterone synthase inhibitor, FDA approved May 2026

Baxdrostat was approved by the FDA in May 2026 as the first aldosterone synthase (CYP11B2) inhibitor for hypertension, and the first mechanistically new antihypertensive class in decades. It differs fundamentally from mineralocorticoid receptor antagonists: rather than blocking the receptor, it inhibits aldosterone PRODUCTION at source, avoiding the compensatory rise in aldosterone that occurs with receptor blockade. In the phase 3 BaxHTN trial, baxdrostat produced clinically substantial systolic reductions on top of standard therapy in uncontrolled and resistant hypertension. Selectivity against cortisol synthesis (CYP11B1) is the key design challenge for this class, and hyperkalaemia remains a monitoring requirement.

Non-adherence must be measured, not guessed — clinicians are poor at detecting it

Objective studies using urine or serum drug-level analysis consistently find that 30-50% of patients referred with resistant hypertension are not taking their medications as prescribed, and that clinician estimation of adherence is little better than chance. Detection methods: high-performance liquid chromatography-tandem mass spectrometry of urine or serum for prescribed drugs (the reference standard); witnessed dosing followed by observed blood pressure response; and prescription refill data. The correct response is non-judgemental exploration of the reasons — side effects, cost, complexity, beliefs about medicines, depression — followed by simplification of the regimen, once-daily single-pill combinations, and shared decision-making, rather than escalation of an unread prescription.

Primary aldosteronism is common in resistant hypertension and is often curable

Primary aldosteronism is present in a substantial minority of resistant hypertension — studies suggest around 20% or more — yet remains dramatically underdiagnosed, with screening rates in eligible patients frequently below 5%. This matters because it is potentially curable by adrenalectomy in unilateral disease, and specifically treatable with mineralocorticoid receptor antagonists in bilateral disease, and because it carries excess cardiovascular and renal risk beyond that explained by blood pressure alone. Screening is by aldosterone-to-renin ratio, which should be performed in all resistant hypertension, hypertension with hypokalaemia, hypertension with adrenal incidentaloma, and hypertension with a family history of early stroke.

Secondary causes and interfering substances

Beyond primary aldosteronism, screen for: obstructive sleep apnoea, which is very common in resistant hypertension and frequently unrecognised; renal artery stenosis, particularly fibromuscular dysplasia in younger women and atherosclerotic disease in older patients; chronic kidney disease; phaeochromocytoma; Cushing syndrome; and coarctation. Substances that raise blood pressure and are routinely missed: NSAIDs, which are among the commonest culprits; combined oral contraceptives; corticosteroids; ciclosporin and tacrolimus; erythropoietin; VEGF inhibitors and tyrosine kinase inhibitors; venlafaxine and other SNRIs; decongestants; liquorice; cocaine and amphetamines; and excessive alcohol. Dietary sodium is the single largest modifiable contributor, and its reduction produces disproportionate benefit in exactly this population.

Key statistics

~10%

of treated hypertensive patients have resistant hypertension

ESC/AHA

30-50%

of apparent resistant hypertension is explained by objectively measured non-adherence

Heart/Hypertension

PATHWAY-2

spironolactone clearly superior to bisoprolol and doxazosin as fourth-line therapy

Lancet 2015

FDA May 2026

baxdrostat approved — first aldosterone synthase inhibitor and first new antihypertensive class in decades

FDA 2026

~20%

of resistant hypertension has primary aldosteronism — screening rates remain under 5%

Endocrine Society/JACC

NSAIDs

among the commonest and most frequently missed causes of drug-induced blood pressure elevation

ESC/AHA

Apparent resistant hypertension — distribution of underlying explanations

Source: ESC/AHA. Most apparent resistance is pseudo-resistance; true resistant hypertension is a minority.

Glossary of key terms

Ambulatory and home blood pressure monitoring
DiagnosisOut-of-office measurement is mandatory before diagnosing resistant hypertension, and predicts cardiovascular outcome better than clinic readings. Ambulatory monitoring over 24 hours provides daytime and night-time averages and reveals the nocturnal dipping pattern: absence of the normal 10-20% nocturnal fall (non-dipping), or a night-time rise (reverse dipping), is independently associated with adverse outcomes and is particularly common in obstructive sleep apnoea, chronic kidney disease, diabetic autonomic neuropathy and primary aldosteronism. Home monitoring requires a validated upper-arm device, correct cuff size, seated rest, and duplicate morning and evening readings over several days with the first day discarded. Wrist and smartphone-based devices are frequently unvalidated and a common source of spurious readings.

Aldosterone-to-renin ratio and confirmatory testing
EndocrinologyThe screening test for primary aldosteronism, calculated from plasma aldosterone and renin measured in the morning in a seated patient after correcting hypokalaemia. Interpretation is complicated by drug effects, which is the principal reason screening is avoided: mineralocorticoid receptor antagonists must be stopped for 4-6 weeks; beta-blockers and clonidine falsely raise the ratio by suppressing renin; ACE inhibitors, ARBs and diuretics falsely lower it by raising renin. Verapamil, hydralazine, doxazosin and moxonidine are relatively neutral and can be substituted. A markedly raised ratio with an elevated aldosterone and spontaneous hypokalaemia may not need confirmatory testing; otherwise saline suppression or captopril challenge is used, followed by CT and — crucially — adrenal vein sampling to distinguish unilateral from bilateral disease before considering surgery.

Renal denervation
InterventionalCatheter-based radiofrequency or ultrasound ablation of renal sympathetic nerves in the renal artery adventitia, aiming to interrupt both afferent and efferent sympathetic signalling. The field followed an instructive trajectory: enthusiastic early uncontrolled results, then the sham-controlled SYMPLICITY HTN-3 trial which was neutral and halted the field, followed by second-generation sham-controlled trials (SPYRAL HTN-OFF MED and ON MED, RADIANCE) with improved technique and patient selection which showed modest but consistent blood pressure reductions. Regulatory approvals followed in 2023. It is now positioned as an adjunctive option for selected patients with genuinely confirmed resistant or uncontrolled hypertension who have adherence verified, secondary causes excluded, and who express a preference for a device-based approach — not as a substitute for medication.

Single-pill combinations and adherence
TherapeuticsAdherence falls as pill count rises, and single-pill combinations are among the most effective structural interventions available in hypertension. Meta-analyses show substantially improved adherence and better blood pressure control with fixed-dose combinations compared with the same drugs given separately. WHO includes fixed-dose combination antihypertensives in the Model List of Essential Medicines and the HEARTS technical package promotes simplified, protocol-driven treatment using them. Practical principles: prefer once-daily dosing; use half-doses of two agents rather than a full dose of one, since efficacy is largely additive while side effects are dose-dependent; and start with combination therapy rather than sequential monotherapy in most patients, which achieves control faster and reduces the therapeutic inertia that leaves patients uncontrolled for years.

Chronotherapy and night-time dosing
Evidence/ControversyWhether taking antihypertensives at night improves outcomes has been genuinely contested. The Hygia Chronotherapy Trial reported dramatic cardiovascular benefit from bedtime dosing, but the effect size was implausibly large and the trial attracted serious methodological criticism. The subsequent TIME trial, a large pragmatic randomised study, found no difference in cardiovascular outcomes between morning and evening dosing, and no safety concerns with either. The practical conclusion is reassuring and simple: patients should take their antihypertensives at whatever time of day they will reliably remember, since adherence matters far more than timing. Specific exceptions where evening dosing may help include nocturnal or non-dipping hypertension confirmed on ambulatory monitoring, and alpha-blockers where postural hypotension is a concern.

Hypertensive emergency versus urgency
Emergency medicineThe distinction rests on evidence of acute target-organ damage, not on the blood pressure number itself. Hypertensive EMERGENCY: severe hypertension with acute damage — hypertensive encephalopathy, intracerebral haemorrhage, acute stroke, acute coronary syndrome, acute pulmonary oedema, aortic dissection, acute kidney injury, retinal haemorrhages with papilloedema, or eclampsia. Requires admission and controlled intravenous reduction, with the specific target depending on the condition: rapid and aggressive reduction in aortic dissection, but cautious and limited reduction in acute ischaemic stroke, where overcorrection worsens cerebral perfusion. Hypertensive URGENCY — severe hypertension without acute organ damage — should be managed with oral therapy and outpatient follow-up; rapid reduction with sublingual nifedipine or similar is harmful and has caused stroke and myocardial infarction.

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Resistant Hypertension

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