Key Facts

Resistant hypertension is defined as blood pressure that remains above target (≥140/90 mmHg clinic or ≥135/85 mmHg ABPM) despite the use of optimal or maximally tolerated doses of three antihypertensive drugs from different classes, one of which should be a diuretic.

Epidemiology

• Affects approximately 10-15% of treated hypertensive patients
• More common in older patients, those with obesity, diabetes, CKD, and Black African/Caribbean ethnicity
• Associated with significantly higher cardiovascular risk compared to controlled hypertension

Aetiology

Pseudo-resistance (most common):

• Poor medication adherence (~50% of apparent resistant cases)
• White coat effect
• Suboptimal drug doses
• Incorrect BP measurement technique

True resistance:

• Volume overload (excess salt intake, inadequate diuretic therapy)
• Secondary hypertension (primary hyperaldosteronism, renal artery stenosis, CKD, phaeochromocytoma, OSA)
• Drug interactions (NSAIDs, oral contraceptives, liquorice, sympathomimetics)
• Obesity and obstructive sleep apnoea

Pathophysiology

• Excess aldosterone-mediated sodium retention is the predominant mechanism in true resistant hypertension
• This explains the efficacy of spironolactone as fourth-line therapy (PATHWAY-2 trial)
• Sympathetic overactivity and arterial stiffness also contribute

Typical Presentation

• Patient on three or more antihypertensives with persistently elevated BP at clinic visits
• Often identified during routine hypertension review
• May present with end-organ damage despite perceived treatment

Features Suggesting Secondary Cause

• Young age (<40 years)
• Sudden onset or worsening of previously controlled BP
• Hypokalaemia (primary hyperaldosteronism)
• Renal impairment or renal bruit (renal artery stenosis)
• Paroxysmal symptoms: headache, sweating, palpitations (phaeochromocytoma)
• Cushingoid features
• Excessive daytime somnolence (OSA)

Red Flags

• Accelerated (malignant) hypertension with papilloedema
• Progressive renal impairment
• Recurrent flash pulmonary oedema
• Labile BP with paroxysmal symptoms
• Hypokalaemia not explained by diuretic use

Bedside

• ABPM/HBPM: confirm true resistance vs white coat effect
• Urinalysis: proteinuria, haematuria
• ECG: LVH, arrhythmia

Bloods

• U&Es: renal function, potassium (low K⁺ suggests hyperaldosteronism)
• Aldosterone:renin ratio: screen for primary hyperaldosteronism
• 24h urinary metanephrines: exclude phaeochromocytoma
• HbA1c, lipid profile: cardiovascular risk
• TFTs: thyroid dysfunction
• Urine/serum drug levels: adherence testing (HPLC-MS/MS)

Imaging

• Renal ultrasound: renal size, asymmetry, obstruction
• Renal artery Doppler/MR angiography: renal artery stenosis
• CT/MRI adrenals: if hyperaldosteronism or phaeochromocytoma suspected
• Echocardiography: LVH, cardiac function

Special Tests

• Directly observed therapy: patient takes medications under supervision, then ABPM
• Saline suppression test/fludrocortisone suppression test: confirm primary hyperaldosteronism
• Adrenal vein sampling: lateralise aldosterone production

Non-pharmacological

• Strict dietary salt restriction (<6g/day)
• Weight loss if obese
• Limit alcohol
• Treat obstructive sleep apnoea with CPAP
• Review and withdraw interfering medications (NSAIDs, OCP)

Pharmacological

NICE Step 4 (CG136):

• Spironolactone 25-50mg OD if K⁺ ≤4.5 mmol/L (first-choice add-on)
• If K⁺ >4.5 mmol/L or spironolactone not tolerated:
  • Alpha-blocker: doxazosin 4-8mg MR OD
  • Beta-blocker: bisoprolol 5-10mg OD
• If still uncontrolled: seek specialist advice

Landmark trials:

• PATHWAY-2: spironolactone superior to doxazosin, bisoprolol, and placebo as add-on for resistant HTN (average BP reduction 8.7 mmHg vs placebo)
• PATHWAY-3: amiloride as effective as spironolactone with fewer side effects

Surgical/Interventional

• Renal denervation: catheter-based sympathetic nerve ablation; investigational
  • SPYRAL HTN-ON MED and RADIANCE-HTN SOLO showed modest BP reductions
  • Not currently recommended by NICE outside clinical trials
• Treat underlying secondary cause surgically where appropriate

Referral Criteria

• All patients with confirmed resistant hypertension should be referred to a hypertension specialist
• Urgent referral if accelerated/malignant hypertension
• Suspected secondary cause requiring further investigation

• Resistant hypertension increases cardiovascular event risk by 50% compared to controlled hypertension
• Higher rates of stroke, MI, heart failure, CKD progression, and cardiovascular death
• With spironolactone addition, ~60% achieve target BP
• Prognosis improves significantly with identification and treatment of secondary causes
• Long-term cardiovascular risk remains elevated even after BP control achieved

Diagnostic Algorithm for Resistant Hypertension

PATHWAY-2 Trial Summary