Resistant and secondary hypertension

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Apparent resistance is much more common than proven resistance. Accurate repeated measurement, out-of-office confirmation, a non-judgemental adherence discussion and a complete medication/substance list often reveal a reversible explanation.

Secondary-cause testing should be phenotype-led but systematic. Hypokalaemia or resistant hypertension suggests primary aldosteronism; abrupt onset/flash pulmonary oedema or creatinine rise after RAAS blockade suggests renovascular disease; snoring/daytime somnolence/obesity suggests OSA.

Drug choice follows physiology and safety. Spironolactone is usually the most effective fourth agent in low-renin/salt-retaining disease, but hyperkalaemia and renal decline can be serious when combined with ACEi/ARB, trimethoprim, NSAIDs or potassium products.

Key points

NICE resistant hypertension means BP remains above the person's age- and comorbidity-appropriate NICE target despite optimal tolerated ACE inhibitor or ARB plus calcium-channel blocker plus thiazide-like diuretic, with elevation confirmed by ABPM or HBPM before step 4.
Before step 4, confirm elevated BP with ABPM or HBPM, assess postural BP and discuss adherence.
Exclude pseudo-resistance: wrong cuff/technique, white-coat effect, missed doses, under-dosing, excess salt/alcohol and pressor medicines/substances.
Common secondary causes include primary aldosteronism, CKD, obstructive sleep apnoea, renovascular disease and medicines; endocrine tumours are less common but important.
If potassium is 4.5 mmol/L or less, consider low-dose spironolactone at step 4, with particular caution in reduced eGFR.
If potassium is above 4.5 mmol/L, consider an alpha-blocker or beta-blocker rather than spironolactone.
Check sodium, potassium and renal function within 1 month of starting further diuretic therapy and whenever illness or interacting medicines increase risk.
If BP remains uncontrolled on optimal four-drug therapy, seek specialist hypertension advice; young onset under 40 also warrants specialist secondary-cause evaluation.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Apparent rather than true resistance

White-coat effect, inaccurate measurement, inconsistent adherence, inadequate dosing or an incomplete drug combination can make controlled or undertreated blood pressure appear pharmacologically resistant.

Renal and renovascular disease

Chronic kidney disease promotes sodium retention and neurohormonal activation, while haemodynamically important renal-artery narrowing can stimulate renin release; abrupt worsening or flash pulmonary oedema increases suspicion.

Endocrine hypertension

Primary aldosteronism causes sodium retention and potassium loss, although potassium may remain normal. Phaeochromocytoma, cortisol excess and thyroid or parathyroid disease are less common phenotype-led considerations.

Sleep, lifestyle and pressor substances

Obstructive sleep apnoea, high sodium or alcohol intake, obesity and medicines or stimulants can sustain sympathetic activity, volume expansion or vasoconstriction despite prescribed therapy.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
A pressor driver persists
Renin-angiotensin activation, mineralocorticoid excess, sympathetic stimulation, renal sodium retention or an exogenous pressor can maintain vasoconstriction, circulating volume or both within the arterial circulation.
2
Pressure remains elevated
Increased systemic vascular resistance and volume-dependent cardiac output sustain arterial pressure, particularly when the treatment combination does not adequately oppose the dominant mechanism.
3
Vascular remodelling develops
Chronic pressure exposure produces arterial wall hypertrophy, endothelial dysfunction and stiffness, reducing vasodilator reserve and making subsequent blood-pressure control more difficult.
4
Target organs remodel
The left ventricle hypertrophies against increased afterload, while renal, cerebral and retinal microvessels undergo pressure-mediated injury and progressive loss of function.
5
A reinforcing cycle follows
Renal damage worsens sodium handling and neurohormonal activation, while unrecognised non-adherence or secondary disease allows the original driver to continue despite additional medicines.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

True resistant hypertension

BP remains above the person's NICE clinic and out-of-office targets despite confirmed adherence to optimal tolerated ACEi/ARB + CCB + thiazide-like diuretic; targets differ with age and clinical context.

Pseudo-resistance

White-coat effect, poor technique, wrong cuff, non-adherence, suboptimal doses/combination, high sodium intake or interfering drugs.

Primary aldosteronism clues

Resistant hypertension, spontaneous or diuretic-induced hypokalaemia, adrenal incidentaloma or disproportionate target-organ damage; potassium may still be normal.

Renovascular/renal clues

CKD, asymmetric kidneys, abdominal bruit, abrupt/worsening hypertension, flash pulmonary oedema or a marked creatinine rise after ACEi/ARB.

OSA and endocrine clues

Loud snoring, witnessed apnoea and sleepiness; paroxysmal headache/palpitations/pallor; cushingoid features; thyroid symptoms; hypercalcaemia.

Young-onset or abrupt severe hypertensionRed flag

Onset under 40, rapid change or extensive organ damage prompts specialist secondary-cause assessment.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
ABPM or structured HBPMFirst step
Why
Confirm sustained out-of-office hypertension and exclude white-coat resistance.
Interpretation and limitations
Use NICE thresholds/averages and check a valid number of readings; normal out-of-office BP means do not escalate solely from clinic values.
02
Observed technique, adherence and medication/substance reconciliation
Why
Detect pseudo-resistance.
Interpretation and limitations
Include NSAIDs, glucocorticoids, combined hormonal contraception, SNRIs, stimulants/decongestants, ciclosporin/tacrolimus, liquorice, cocaine/amphetamines and salt products.
03
U&E/eGFR, urinalysis and urine ACR
Why
Identify renal disease and establish safety for RAAS blockade/diuretics.
Interpretation and limitations
Hypokalaemia raises aldosterone suspicion; albuminuria/haematuria or falling eGFR directs renal evaluation.
04
Aldosterone-renin ratio
Why
Screen for primary aldosteronism in a suitable phenotype.
Interpretation and limitations
Correct hypokalaemia and interpret with posture/time, sodium status and interfering medicines; a positive screen requires specialist confirmatory/subtype evaluation.
05
Sleep study or home respiratory polygraphy
Why
Confirm obstructive sleep apnoea when symptoms/risk are present.
Interpretation and limitations
Treating OSA improves symptoms and may modestly lower BP; antihypertensive treatment is still required.
06
Targeted renal-artery/endocrine imaging and biochemical tests
Why
Investigate renovascular disease, phaeochromocytoma, Cushing syndrome, thyroid/parathyroid disease or coarctation.
Interpretation and limitations
Order after clinical/biochemical selection; do not use indiscriminate imaging as a substitute for specialist interpretation.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

White-coat hypertension

Repeated clinic elevation with normal structured home or ambulatory readings indicates a white-coat effect and argues against escalating treatment solely from consultation measurements.

Measurement or adherence problem

An unsuitable cuff, poor technique, missed tablets or adverse-effect avoidance can mimic resistance; technique and device checks, dispensing history and a non-judgemental medicines discussion provide clues.

Primary aldosteronism

Resistant hypertension, spontaneous or diuretic-associated hypokalaemia, an adrenal incidentaloma or disproportionate organ damage supports screening, but normal potassium does not exclude it.

Renovascular disease

Abrupt onset or worsening, asymmetric kidneys, an abdominal bruit, flash pulmonary oedema or marked renal decline after renin-angiotensin blockade suggests renal-artery disease.

Obstructive sleep apnoea

Loud snoring, witnessed pauses, unrefreshing sleep and daytime somnolence in an appropriate phenotype favour sleep-disordered breathing, confirmed through targeted sleep assessment.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01confirmApparent resistant hypertensionFirst stepClinic BP remains above target on three-drug treatment.

1First: repeat correct seated and standing BP, check cuff/device and obtain ABPM or HBPM.
2Next: reconcile prescriptions, actual dosing, adverse effects, cost/access, salt/alcohol and all pressor substances in a non-judgemental interview.
3Next: confirm optimal tolerated ACEi/ARB + CCB + thiazide-like diuretic and review renal function/electrolytes.
4EscalationEscalation: only label true resistance and move to step 4 when out-of-office elevation and adherence are supported.

02secondary causesPhenotype-led investigationConfirmed resistance, young onset, abrupt worsening, hypokalaemia or other specific clues.

1First: U&E/eGFR, urinalysis/ACR, glucose/HbA1c, lipids and target-organ assessment.
2Next: screen for primary aldosteronism and OSA when indicated; review kidney disease and medicines/substances in every patient.
3Next: arrange specialist metanephrines, cortisol testing, renal-artery imaging, thyroid/calcium tests or coarctation assessment from the phenotype.
4EscalationEscalation: same-day assessment for suspected phaeochromocytoma symptoms with severe/labile BP or any hypertensive emergency feature.

03step 4Add a fourth agentTrue resistant hypertension after optimal A+C+D treatment.

1First: if potassium is 4.5 mmol/L or less, consider spironolactone 25 mg once daily; use particular caution with reduced eGFR.
2Next: if potassium exceeds 4.5 mmol/L or spironolactone is unsuitable, consider an alpha-blocker or beta-blocker selected for comorbidity.
3Next: check sodium, potassium and renal function within 1 month and after dose/interacting-drug changes.
4EscalationEscalation: reduce/stop and seek advice for significant hyperkalaemia, renal decline, symptomatic hypotension or endocrine adverse effects.

04specialistUncontrolled on four drugsBP remains above target on confirmed optimal tolerated step-4 treatment.

1First: re-check out-of-office BP and adherence rather than assuming pharmacological failure.
2Next: refer to a specialist hypertension service for supervised investigation, medication optimisation and secondary-cause treatment.
3Next: address sleep apnoea, obesity, sodium/alcohol and causative medicines alongside pharmacotherapy.
4EscalationEscalation: investigate target-organ progression and use the emergency pathway for any acute injury.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Preferred additional diuretic at NICE step 4 when potassium is 4.5 mmol/L or less.

Spironolactone

25 mg orally once daily initially; increase to 50 mg once daily if needed and tolerated.

Off-label for resistant hypertension. Avoid/seek specialist advice with significant renal impairment; monitor potassium/eGFR within 1 month. Hyperkalaemia risk rises with ACEi/ARB, trimethoprim, NSAIDs, potassium supplements/salt substitutes. Can cause gynaecomastia/menstrual effects.

Alpha-blocker option at step 4, particularly when potassium is above 4.5 mmol/L or spironolactone is unsuitable.

Doxazosin

Immediate-release: 1 mg orally once daily initially, titrated to 2–4 mg once daily; maximum 16 mg/day.

First-dose and postural hypotension, dizziness and falls; start low, often at bedtime, and review standing BP. May benefit coexisting prostate symptoms.

Beta-blocker step-4 alternative when clinically suitable, especially with a separate indication such as angina or rate control.

Bisoprolol

For the licensed hypertension indication, start 5 mg orally once daily; the usual dose is 10 mg once daily and the SmPC maximum is 20 mg once daily. A lower start may be selected for an older or vulnerable patient.

Bradycardia, heart block, bronchospasm and masking hypoglycaemia; do not stop abruptly after chronic use. Do not exceed 10 mg/day in severe renal or hepatic impairment under the cited SmPC.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Stroke and hypertensive brain injury

Sustained pressure accelerates small-vessel disease and atherosclerosis, increasing ischaemic and haemorrhagic stroke risk; abrupt severe elevation with organ injury may cause encephalopathy.

Coronary disease and heart failure

Increased afterload causes left-ventricular hypertrophy and higher oxygen demand, while endothelial injury accelerates coronary disease, eventually contributing to ischaemia, diastolic dysfunction or systolic failure.

Chronic kidney disease

Glomerular and small-artery injury cause albuminuria and declining filtration. Renal impairment then promotes further sodium retention, making hypertension progressively harder to control.

Hypertensive retinopathy

Retinal arteriolar damage can progress from narrowing to haemorrhage, exudation and optic-disc swelling, providing visible evidence of systemic microvascular injury.

Aortic and peripheral vascular disease

Chronic wall stress and accelerated atherosclerosis increase the likelihood of aortic syndromes, aneurysmal disease and limb ischaemia, particularly when other vascular risks coexist.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Use ABPM/HBPM to document response and identify nocturnal/masked patterns rather than relying only on clinic BP.
Measure seated and standing BP after additions/titration, especially with alpha-blockers, older age or falls.
Check sodium, potassium and creatinine/eGFR within 1 month of spironolactone/further diuretic therapy and sooner in high-risk patients.
Review adherence, NSAIDs/trimethoprim/salt substitutes and intercurrent vomiting/diarrhoea or AKI at every safety contact.
Track target-organ markers: urine ACR/eGFR, ECG/LVH, retinal findings and overall CVD risk.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Normal potassium does not exclude aldosteronism

Many patients with primary aldosteronism are normokalaemic; resistant hypertension itself is a screening clue.

The A+C+D backbone matters

Resistance is not established if the regimen lacks a RAAS blocker, CCB and thiazide-like diuretic at tolerated effective doses without a reason.

Ask how tablets are actually taken

A collaborative account of missed doses and adverse effects is more useful than the prescription record alone.

ARR is medication-sensitive

Do not interpret a ratio without knowing beta-blocker, diuretic, RAAS-blocker and mineralocorticoid-antagonist effects; use specialist preparation when possible.

Salt can overpower the regimen

High sodium intake promotes volume expansion and blunts RAAS blocker/diuretic response; dietary assessment is treatment, not an afterthought.

11Common pitfallsFrequent interpretation and management errors.

01
Adding a fourth drug before confirming ABPM/HBPM and adherence.
02
Starting spironolactone when potassium is above 4.5 mmol/L without specialist justification.
03
Forgetting trimethoprim, NSAIDs and potassium salt substitutes when investigating hyperkalaemia.
04
Assuming normal potassium excludes primary aldosteronism.
05
Ordering broad endocrine imaging before biochemical/phenotypic selection.