Resistant Hypertension

Resistant hypertension is blood pressure that stays over target despite three antihypertensive drugs of different classes at maximally tolerated doses. The three include a long acting calcium channel blocker, a blocker of the renin angiotensin system and a thiazide like diuretic.

Blood pressure controlled only on four or more drugs also counts.

About 10 to 15% of treated hypertensive adults have apparent resistant hypertension. True resistance is less frequent.

Pseudo resistance is common and must be excluded first: non-adherence, white coat effect, poor technique, inadequate dosing, pseudohypertension and interfering substances.

It carries a higher risk of stroke, heart failure, kidney disease and death.

Pathophysiology. Volume expansion with sodium sensitivity, aldosterone excess, sympathetic overactivity and arterial stiffness drive it.

Obesity, sleep apnoea, chronic kidney disease and high salt intake add to it. Primary aldosteronism is the commonest secondary cause.

• Usually asymptomatic. Headache, visual change, dyspnoea or chest pain suggest organ damage.
• History to elicit: adherence, pill burden, salt intake, alcohol, khat, herbal remedies, anti-inflammatory drugs, oral contraceptives, steroids, decongestants, ciclosporin and tacrolimus, antidepressants (venlafaxine, bupropion), stimulants and liquorice.
• Features of secondary causes: muscle weakness, nocturia and polyuria (aldosteronism), snoring and daytime sleepiness, abdominal bruit, paroxysmal headache with sweating and palpitation, central obesity and striae, radio femoral delay.
• Target organ damage: left ventricular hypertrophy, retinopathy, albuminuria, reduced eGFR.

Red flags.

• Blood pressure of 180/120 mm Hg or more with organ damage
• Spontaneous hypokalaemia, or an adrenal mass
• Creatinine rise of over 30% after starting an ACE inhibitor or angiotensin receptor blocker
• Flash pulmonary oedema
• Paroxysmal hypertension with sweating and palpitation
• Onset under 30 years, or abrupt worsening
• Pregnancy

• Confirm resistance. Validated upper arm device with the correct cuff size, both arms, and ambulatory monitoring (daytime 135/85 mm Hg or more) or home monitoring (135/85 mm Hg or more).
• Adherence. Pharmacy refill records, pill counts, urine or plasma drug level testing, or witnessed drug intake with repeat blood pressure after 2 to 4 hours.
• Baseline tests. Electrolytes, creatinine, eGFR, urinalysis, urine albumin to creatinine ratio, glucose, lipids, calcium, TSH, ECG, echocardiography, fundoscopy.
• Primary aldosteronism. Morning aldosterone and renin after correcting potassium, seated 5 to 15 minutes after being up for 2 hours. A suppressed renin with aldosterone over 10 ng/dL (280 pmol/L) is suggestive. Stop mineralocorticoid antagonists and amiloride 4 weeks before when feasible. Confirm with a saline infusion test (2 L of 0.9% saline over 4 hours), then adrenal CT, with adrenal vein sampling before surgery in most patients.
• Sleep apnoea. Home sleep study or polysomnography.
• Renal artery disease. Renal artery duplex, CT or MR angiography when features suggest it (young woman with fibromuscular dysplasia, flash pulmonary oedema, atherosclerosis).
• Phaeochromocytoma. Plasma free metanephrines (supine) or 24-hour urinary fractionated metanephrines.
• Cushing syndrome. Overnight 1 mg dexamethasone suppression test, late night salivary cortisol or 24-hour urinary free cortisol.
• Renal parenchymal disease. Renal ultrasound.

Differential diagnosis.

• Pseudo resistance: non-adherence, white coat effect, inadequate regimen or dose, wrong cuff size, pseudohypertension
• Interfering drugs and substances (anti-inflammatory drugs, khat, stimulants, steroids, ciclosporin, oral contraceptives)
• Primary aldosteronism
• Obstructive sleep apnoea
• Chronic kidney disease and renovascular disease
• Phaeochromocytoma and paraganglioma
• Cushing syndrome, thyroid disease, hyperparathyroidism, acromegaly
• Coarctation of the aorta and monogenic hypertension

• Remove contributors. Stop interfering drugs and khat, limit alcohol, sodium under 2 g daily (salt under 5 g), weight loss and exercise. Use once daily single pill combinations to improve adherence.
• Optimise triple therapy at full doses.
  • Ramipril 2.5 mg orally once daily, increased every 2 to 4 weeks to 10 mg once daily (maximum 10 mg daily, and 5 mg daily at creatinine clearance under 30 mL/min). Check potassium and creatinine 1 to 2 weeks after each change. Contraindicated in pregnancy and bilateral renal artery stenosis. Telmisartan 40 mg orally once daily, increased to 80 mg (maximum 80 mg daily), is contraindicated in pregnancy and bilateral renal artery stenosis, with potassium and creatinine checked 1 to 2 weeks after each change. Never combine the two.
  • Amlodipine 5 mg orally once daily, increased to 10 mg (maximum 10 mg daily; start 2.5 mg in older adults and liver impairment).
  • Chlortalidone 12.5 mg orally once daily, increased to 25 mg (maximum 50 mg daily), or indapamide modified release 1.5 mg once daily (maximum 1.5 mg daily; avoid at eGFR under 30 mL/min/1.73 m2). Replace hydrochlorothiazide with these. Check sodium, potassium and creatinine at 2 weeks and 3 months. At eGFR under 30 mL/min/1.73 m2 or with volume overload use furosemide 40 mg orally twice daily (higher doses under specialist care).
• Fourth drug.
  • Spironolactone 25 mg orally once daily, increased to 50 mg once daily (maximum 50 mg daily in this setting). Check potassium and creatinine at 1 week and 4 weeks, then every 3 months. Withhold at potassium over 5.5 mmol/L and avoid at eGFR under 30 mL/min/1.73 m2.
  • For gynaecomastia: eplerenone 50 mg orally once daily, increased to 50 mg twice daily (maximum 100 mg daily). Contraindicated with strong CYP3A4 inhibitors and at potassium over 5.5 mmol/L.
  • Alternative: amiloride 5 mg orally once daily, increased to 10 mg (maximum 20 mg daily), with potassium and creatinine at 1 week and 4 weeks, withheld at potassium over 5.5 mmol/L and avoided at eGFR under 30 mL/min/1.73 m2.
• Fifth and later drugs (specialist care).
  • Bisoprolol 2.5 mg orally once daily, increased to 5 to 10 mg once daily, maximum 20 mg daily (do not exceed 10 mg daily at creatinine clearance under 20 mL/min or in severe liver impairment), when heart rate is over 70/min or an indication is present.
  • Doxazosin 1 mg orally at night, doubled every 1 to 2 weeks to 4 to 8 mg, maximum 16 mg daily. First dose hypotension. Avoid in heart failure.
  • Hydralazine 25 mg orally twice daily, increased to 100 mg twice daily (maximum 200 mg daily), with a beta blocker and a diuretic. Contraindicated in systemic lupus erythematosus and aortic dissection.
  • Minoxidil 2.5 mg orally twice daily, increased no faster than every 3 days to 10 to 40 mg daily (maximum 100 mg daily), only with a loop diuretic and a beta blocker, as a last resort. It causes fluid retention, hirsutism and pericardial effusion.
  • Clonidine can cause rebound hypertension on abrupt withdrawal.
• Secondary causes.
  • Primary aldosteronism: adrenalectomy for unilateral disease. For bilateral disease, spironolactone 25 mg orally once daily, increased every 4 weeks to 100 mg daily (maximum 100 mg in this setting) until renin is no longer suppressed, with potassium monitoring.
  • Sleep apnoea: continuous positive airway pressure and weight loss, which lower blood pressure modestly.
  • Renal artery stenosis: medical therapy first. Angioplasty for fibromuscular dysplasia, and stenting of atherosclerotic disease only for flash pulmonary oedema, refractory hypertension or progressive renal decline.
  • Phaeochromocytoma, Cushing syndrome, coarctation, hyperparathyroidism and thyroid disease: specialist treatment. In phaeochromocytoma start alpha blockade before any beta blocker.
• Renal denervation is an option in selected patients after specialist review where available, lowering office systolic pressure by roughly 5 to 10 mm Hg.
• Statin and aspirin by cardiovascular risk (aspirin only for established vascular disease).

Special groups.

• Black patients: respond best to a calcium channel blocker plus a thiazide like diuretic, and to spironolactone. ACE inhibitor monotherapy is less effective.
• Pregnancy: stop ramipril, telmisartan, spironolactone and statins. Use labetalol, modified release nifedipine or methyldopa.
• Older adults: avoid orthostatic hypotension and titrate slowly.

Monitoring. Home and clinic blood pressure every 2 to 4 weeks until at target, then every 3 to 6 months. Ambulatory monitoring yearly. Potassium and creatinine 1 to 2 weeks after each change of ramipril or telmisartan and at 1 week and 4 weeks after starting spironolactone, then every 3 months, and sodium at 2 weeks and 3 months after starting a diuretic. Repeat the adherence check at each visit.

Referral and escalation. Refer to a hypertension specialist when blood pressure is uncontrolled on four drugs, a secondary cause is suspected, or the patient is under 40 years. Urgent for hypertensive emergency.