Resistant hypertension

Resistant hypertension is office blood pressure that stays at or over target despite three antihypertensive drugs of different classes at maximally tolerated doses, one of which is a diuretic.

The thresholds are 140/90 mmHg or more, and 130/80 mmHg or more in diabetes and chronic kidney disease. The usual drugs are an ACE inhibitor or angiotensin receptor blocker, a calcium channel blocker and a thiazide like diuretic.

Adherence must be confirmed, and an out of office measurement must also exceed target.

Pressure that is controlled only with four or more drugs is also called resistant (controlled resistant hypertension). Refractory hypertension is the rarer state in which pressure remains uncontrolled on five or more drugs, including chlortalidone and spironolactone.

Clinical relevance. About 10% to 15% of treated hypertensive adults meet the definition, and the figure is higher in older adults, people of African ancestry, diabetes and chronic kidney disease. Risk of stroke, heart failure, kidney failure and death is higher than in controlled hypertension. A large share of apparent resistance is not true resistance, so pseudoresistance must be excluded first; a secondary cause is then sought (found in 10% to 30% of true resistance).

Classification.

• Pseudoresistance: white coat effect (clinic pressure high, ambulatory pressure normal in 20% to 30% of apparent cases), poor measurement technique, cuff too small, pseudohypertension from calcified arteries, non adherence (30% to 50%), inadequate doses, inappropriate combinations, clinical inertia.
• True resistance, secondary: primary aldosteronism, obstructive sleep apnoea, chronic kidney disease, renal artery stenosis, phaeochromocytoma, Cushing syndrome, thyroid and parathyroid disease, coarctation, drugs and substances.
• True resistance, primary: sodium retention, obesity related and low renin hypertension, arterial stiffness, sympathetic overactivity.

Mechanism. Volume expansion (excess salt intake, inadequate diuretic, kidney disease) is the commonest driver, followed by mineralocorticoid excess (aldosterone excess occurs in up to 20% of resistant cases), sympathetic activation (sleep apnoea, obesity) and drugs that retain sodium or raise vascular tone.

History.

• Blood pressure history: duration, home readings, highest values, response to previous drugs, side effects, emergency visits.
• Adherence: every drug, dose and timing; missed doses; cost, side effects, pill burden, health beliefs, cognitive problems, use of pill organisers; ask without blame ("how many doses do you miss in a typical week?").
• Diet and lifestyle: salt intake (processed food, stock cubes, bread, canned food, pickles, fish sauces), alcohol (over 14 units a week), liquorice, caffeine, weight change, physical activity, smoking.
• Interfering drugs and substances: NSAIDs (including topical and over the counter), corticosteroids, oral contraceptives and hormone therapy, decongestants (pseudoephedrine, phenylephrine), stimulants (methylphenidate, amphetamines, cocaine, caffeine tablets, energy drinks).
• Also antidepressants (venlafaxine, tricyclics), ciclosporin, tacrolimus, erythropoietin, tyrosine kinase and VEGF inhibitors, herbal products (liquorice, ephedra, ginseng, yohimbine), and anabolic steroids.
• Secondary clues: loud snoring, witnessed apnoeas, daytime sleepiness.
• Muscle weakness, cramps, nocturia (hypokalaemia in aldosteronism).
• Episodic headache, sweating, palpitations, pallor (phaeochromocytoma).
• Weight gain, bruising, striae, proximal weakness, mood change (Cushing syndrome).
• Haematuria, foamy urine, family history of kidney disease.
• Flash pulmonary oedema or fall in kidney function on an ACE inhibitor (renal artery stenosis).
• Leg claudication, headache, cold legs (coarctation).
• Heat intolerance, weight loss (hyperthyroidism).
• Kidney stones, bone pain (hyperparathyroidism).
• Early onset (under 40) or sudden worsening of previously controlled pressure.

Examination.

• Blood pressure measured properly: seated, rested 5 minutes, correct cuff (bladder encircling 80% of arm), two readings 1 to 2 minutes apart, both arms at the first visit; a difference over 15 mmHg suggests subclavian or aortic disease. Standing pressure at 1 and 3 minutes. Radio femoral delay.
• Weight, body mass index, waist, neck circumference (over 43 cm in men, 41 cm in women suggests sleep apnoea), Mallampati score.
• Cushingoid features, thyroid, abdominal and renal bruits, flank masses (polycystic kidneys), peripheral pulses, signs of heart failure and left ventricular hypertrophy, fundoscopy (retinopathy grade, papilloedema).
• Skin: neurofibromas and café au lait spots (neurofibromatosis with phaeochromocytoma), striae.

Red flags.

• Blood pressure 180/120 mmHg or more with headache, visual change, chest pain, breathlessness, confusion or new neurological signs.
• Hypokalaemia (potassium under 3.5 mmol/L) off diuretics, or spontaneous hypokalaemia.
• Paroxysmal hypertension with headache, sweating and palpitations.
• Abdominal bruit, kidney function falling after an ACE inhibitor or angiotensin receptor blocker, flash pulmonary oedema.
• Age under 40, differential arm and leg pressures, weak femoral pulses.
• Rapid kidney function decline, haematuria or heavy proteinuria.
• Pregnancy.

Pseudoresistance. White coat effect, wrong cuff size, poor technique, calcified brachial artery (pseudohypertension, positive Osler manoeuvre), non adherence, under dosing, no diuretic, inappropriate combination (for example an ACE inhibitor with an angiotensin receptor blocker, or a beta blocker with verapamil), high salt intake that defeats treatment.

Secondary causes.

• Primary aldosteronism (unilateral adenoma, bilateral hyperplasia, glucocorticoid remediable aldosteronism).
• Obstructive sleep apnoea (present in 60% to 80% of resistant hypertension).
• Chronic kidney disease and renal parenchymal disease (glomerulonephritis, diabetic nephropathy, polycystic kidney disease, reflux nephropathy, schistosomal nephropathy).
• Renal artery stenosis (atherosclerotic in older adults; fibromuscular dysplasia in younger women; Takayasu arteritis).
• Phaeochromocytoma and paraganglioma; Cushing syndrome; thyroid disease; hyperparathyroidism; acromegaly; congenital adrenal hyperplasia; Liddle syndrome; apparent mineralocorticoid excess.
• Coarctation of the aorta (including repaired).
• Drugs and substances and alcohol excess.
• Obesity, high sodium intake, and aortic stiffness.

Conditions that mimic crisis within resistant hypertension. Pain, anxiety and panic, acute withdrawal of clonidine or beta blocker, cocaine or amphetamine use, urinary retention, raised intracranial pressure.

1. Confirm true resistance: validated 24 hour ambulatory blood pressure monitoring (daytime average 135/85 mmHg or more) or home monitoring (twice daily for 7 days, average 135/85 mmHg or more) with a validated device and correct cuff.
2. Check adherence objectively: pharmacy refill records, pill counts, directly observed dosing for a period, and where available urine or plasma drug level screens by liquid chromatography and mass spectrometry. Non adherence is found in 30% to 50% of apparent resistance.
3. Review and withdraw or reduce interfering drugs and substances, and confirm drug doses and combinations.
4. Estimate dietary salt: 24 hour urinary sodium (over 100 mmol, about 2.3 g sodium or 6 g salt, a day means high intake).
5. Basic tests: urea, creatinine, eGFR, sodium, potassium, calcium, glucose or HbA1c, lipids, thyroid stimulating hormone, full blood count, urinalysis, urine albumin to creatinine ratio, 12 lead ECG, echocardiography.
6. Screen for primary aldosteronism in every resistant patient.
   • Aldosterone to renin ratio midmorning, after correcting potassium, with the patient seated for 5 to 15 minutes.
   • Positive when aldosterone is over 10 ng/dL, or about 300 pmol/L, with a ratio over 20 to 30 ng/dL for each ng/mL/hour and suppressed renin.
   • Stop spironolactone and eplerenone for 4 to 6 weeks if possible, though a suppressed renin on treatment still permits interpretation.
   • Confirm with saline infusion or captopril challenge; CT of adrenals; adrenal vein sampling to lateralise before surgery.
7. Sleep study (home polygraphy or polysomnography) when snoring, obesity, Epworth score over 10 or nocturnal hypertension.
8. Renal imaging: renal ultrasound for size and asymmetry (over 1.5 cm difference); duplex ultrasound, CT or MR angiography for renal artery stenosis if features suggest it.
9. Plasma free metanephrines (supine) or 24 hour urinary fractionated metanephrines when paroxysms, adrenal incidentaloma, family history or genetic syndrome; late night salivary cortisol, overnight 1 mg dexamethasone suppression test (08:00 cortisol under 50 nmol/L excludes) or 24 hour urinary free cortisol for Cushing syndrome.
10. Echocardiography or CT or MR angiography for coarctation in young patients with differential pressures.

Limits. Home readings are unreliable if technique or device is wrong. Aldosterone to renin ratio is altered by drugs (beta blockers lower renin, giving false positives; ACE inhibitors, angiotensin receptor blockers, diuretics and dihydropyridines raise renin, giving false negatives), potassium and sodium intake. Adrenal imaging may show non functioning incidentalomas. Drug level screens are not available everywhere.

Step 1. Remove pseudoresistance and reversible factors.

• Correct measurement and use out of office readings.
• Stop or reduce interfering drugs (NSAIDs, decongestants, stimulants, steroids where possible, liquorice, oral oestrogen contraceptives where pressure is the problem).
• Reduce salt to under 5 g a day (2 g sodium); weight loss (about 1 mmHg for each kilogram); alcohol under 14 units a week; regular aerobic exercise 150 minutes a week; a diet rich in fruit, vegetables, legumes and low fat dairy (potassium rich) if kidney function allows.
• Improve adherence: once daily regimens, single pill combinations, fixed schedules, pill organisers, reminders, address cost, side effects and beliefs, home monitoring, and involve family or a pharmacist.

Step 2. Optimise the three drug base at full doses.

• ACE inhibitor or angiotensin receptor blocker at maximum tolerated dose: ramipril 10 mg daily (maximum 20 mg), lisinopril 40 mg daily, perindopril 8 to 16 mg daily, losartan 100 mg daily, valsartan 320 mg daily, telmisartan 80 mg daily, candesartan 32 mg daily.
• Calcium channel blocker: amlodipine 10 mg daily, or nifedipine modified release 60 to 90 mg daily, or lercanidipine 20 mg daily.
• Diuretic: chlortalidone 25 mg daily (up to 50 mg), or indapamide 2.5 mg daily, or hydrochlorothiazide 25 mg to 50 mg daily.
• In eGFR under 30 mL/min/1.73 m2 use chlortalidone 12.5 to 25 mg or a loop diuretic (furosemide 40 to 80 mg twice daily or torasemide 10 to 40 mg daily).
• Check sodium, potassium, urate and creatinine at 1 to 2 weeks.
• Single pill combinations (for example perindopril with amlodipine and indapamide) improve adherence.

Step 3. Add a fourth drug, preferably a mineralocorticoid receptor antagonist.

• Spironolactone 25 mg daily, increased to 50 mg daily after 4 weeks (maximum about 100 mg for resistant hypertension). It is effective in true resistance whatever the renin level.
• Check potassium and creatinine at 1 week and 4 weeks, then every 3 to 6 months. Avoid when potassium is over 4.5 mmol/L at baseline or eGFR is under 30 unless closely monitored. Stop when potassium exceeds 5.5 mmol/L.
• Gynaecomastia, breast tenderness and erectile dysfunction occur (switch to eplerenone 50 mg daily, increasing to 100 mg).
• If a mineralocorticoid receptor antagonist is not tolerated, alternatives are amiloride 5 to 10 mg daily (monitor potassium) or bisoprolol 5 to 10 mg daily.
• Alternatively, doxazosin 1 mg at night increasing to 4 to 8 mg (orthostatic hypotension; not for heart failure).
• Alternatively, clonidine 0.05 to 0.1 mg twice daily increasing to 0.3 mg twice daily (rebound on stopping; avoid with a beta blocker).
• Alternatively, hydralazine 25 mg twice daily increasing to 100 mg twice daily (with a beta blocker and diuretic to control reflex tachycardia and fluid retention).
• Alternatively, minoxidil 2.5 mg daily increasing to 10 to 40 mg daily (specialist use; needs a loop diuretic and a beta blocker; causes hirsutism, fluid retention, pericardial effusion).
• Beta blocker is added when there is coronary disease, heart failure, arrhythmia or fast resting heart rate: bisoprolol 2.5 to 10 mg daily, or carvedilol 12.5 to 25 mg twice daily, or nebivolol 5 mg daily.

Step 4. Treat the secondary cause.

• Primary aldosteronism: unilateral adenoma, laparoscopic adrenalectomy (cures or improves pressure in most; stop potassium sparing drugs after careful monitoring); bilateral disease, spironolactone 25 to 100 mg daily (up to 400 mg) or eplerenone 50 to 200 mg daily.
• Obstructive sleep apnoea: continuous positive airway pressure (lowers pressure by 2 to 7 mmHg), weight loss, mandibular advancement device, surgery in selected cases.
• Chronic kidney disease: ACE inhibitor or angiotensin receptor blocker, a loop diuretic, sodium restriction, dialysis volume control.
• Renal artery stenosis: optimise medicines; stenting is reserved for flash pulmonary oedema, resistant hypertension with progressive kidney function loss and bilateral or solitary kidney disease; fibromuscular dysplasia, angioplasty.
• Phaeochromocytoma: alpha blockade first (phenoxybenzamine 10 mg twice daily increasing to 1 mg/kg daily or doxazosin 2 to 16 mg daily), then beta blocker, then surgery with high salt and fluid intake before operation.
• Cushing syndrome, hyperparathyroidism, thyroid disease, acromegaly and coarctation: specific surgery, medicines or intervention.

Device therapy. Catheter based renal denervation (radiofrequency or ultrasound) produces an average fall in 24 hour systolic pressure of about 5 to 10 mmHg in selected resistant patients; it is offered in specialist centres only after exclusion of secondary causes and non adherence. Baroreflex activation therapy is investigational. Cardiovascular protection. Atorvastatin 20 to 80 mg daily by risk; aspirin 75 mg daily only in established cardiovascular disease; glucose control; stop smoking.

Monitoring. Review every 2 to 4 weeks until controlled (home or ambulatory confirmation), then every 3 to 6 months. Check potassium and creatinine 1 to 2 weeks after every change in a renin angiotensin or aldosterone blocker or diuretic, and every 3 to 6 months on spironolactone. Annual urine albumin to creatinine ratio, ECG, echocardiography for hypertrophy every 1 to 3 years, fundoscopy.

Referral and escalation. Specialist hypertension clinic when pressure is uncontrolled on four drugs including spironolactone, or when a secondary cause is suspected; nephrology for kidney disease or renal artery disease; endocrinology for adrenal and thyroid disease; sleep medicine; cardiology for heart disease; interventional radiology or vascular surgery for renal artery disease.

Admission. Blood pressure 180/120 mmHg or more with signs of acute organ damage, acute heart failure, acute kidney injury, or severe uncontrolled pressure with symptoms.

Safety netting. Return urgently for severe headache, chest pain, breathlessness, visual loss, weakness, speech difficulty, confusion, fits, or pressure over 180/120 mmHg with symptoms. Do not stop drugs suddenly (rebound hypertension with clonidine and beta blockers). Report muscle weakness, palpitations or vomiting on spironolactone, ACE inhibitors or diuretics, and avoid NSAIDs and potassium supplements.

Special groups. Older adults: treat gradually, avoid orthostatic hypotension, check for pseudohypertension. Pregnancy: resistant disease needs specialist care; avoid ACE inhibitors, angiotensin receptor blockers and spironolactone; use labetalol, nifedipine and methyldopa. People of African ancestry: higher prevalence, with volume dependent low renin disease; calcium channel blockers, thiazide like diuretics and spironolactone work well. Chronic kidney disease and diabetes: stricter targets under 130/80 mmHg and closer potassium monitoring.

HIV: check antiretroviral interactions with calcium channel blockers. Endemic regions: schistosomal and glomerular kidney disease, salt rich diets and limited drug access contribute; fixed dose combinations improve outcomes.