Resistant & Secondary Hypertension (ISH 2026)
Uncontrolled BP is most often due to clinical inertia or non-adherence. Rule those out before labelling the patient resistant.
Step 1 — Define apparent resistant hypertension
sOBP ≥140/90 mmHg on ≥3 antihypertensive drugs at optimal or maximally tolerated doses, including a diuretic.
About 50% of people labelled resistant have pseudo-resistance. True resistant hypertension affects 5–10% of hypertensives and carries high CV risk.
Step 2 — Exclude pseudo-resistance (ESSENTIAL)
Check each:
- Non-standardised office BP — repeat with full sOBP protocol (
ish-htn-diagnosis-bp-measurement)
- White-coat effect — confirm with home or ambulatory BP (OPTIMAL: use sHBPM/ABPM to diagnose true resistance)
- Non-adherence — ask, pill counts, refill data; drug detection in urine/plasma if available
- Suboptimal regimen — wrong doses, no diuretic, wrong diuretic for eGFR
- Substance/drug-induced — NSAIDs, high-dose paracetamol, combined OCP, SNRIs/MAOIs/tricyclics, VEGF/TKIs, ciclosporin, decongestants, stimulants, ADHD drugs, glucocorticoids, EPO/HIF inhibitors, triptans, excess caffeine/energy drinks, liquorice, ephedra, St John's wort, yohimbine, ginseng
- Secondary hypertension (Step 5)
Reduce or remove BP-raising substances where possible. If they are needed, treat BP to target anyway.
Step 3 — Optimise treatment (ESSENTIAL)
- Lifestyle (especially salt) + review adherence
- Diuretic-based regimen at maximally tolerated doses — loop diuretic or chlorthalidone if eGFR <30
- Add low-dose spironolactone as the 4th drug if K⁺ <4.5 mmol/L and eGFR ≥30, with close K⁺/eGFR monitoring
- Add any available class not already in use
- Simplify — single pills, once daily
OPTIMAL — if spironolactone not tolerated or BP still high:
- Amiloride, eplerenone, beta-blocker, clonidine, doxazosin, sacubitril/valsartan
- New classes (approval and availability vary by country):
- Aldosterone synthase inhibitors — baxdrostat (approved for uncontrolled/resistant), lorundrostat (under review). Watch hyperkalaemia (worse in CKD) and hyponatraemia — monitor K⁺ and Na⁺
- Endothelin receptor antagonist — aprocitentan (approved in some regions). Watch fluid retention, oedema, weight gain, heart failure — more in CKD and pre-existing CVD
- Non-steroidal MRA — esaxerenone (Japan). K⁺ and renal monitoring as other RAAS inhibitors
- Angiotensinogen siRNA — zilebesiran (not yet marketed; 6-monthly SC). Effect can't be switched off — hypotension, renal change, hyperkalaemia risks
- Refer to an expert centre for further investigation and titration
Step 4 — Renal denervation (OPTIMAL, expert centres only)
BP fall similar to one extra drug; not all patients respond.
Indications:
- True resistant hypertension uncontrolled on ≥4 drugs at max tolerated doses (ACEi/ARB + CCB + thiazide/thiazide-like + aldosterone-targeting drug), or
- Uncontrolled on fewer drugs because of intolerable side effects
Requirements:
- Non-adherence, white-coat effect (24-h ABPM) and secondary hypertension excluded
- eGFR ≥40
- No renal artery abnormalities
- CV risk, life expectancy and preferences considered
- Expert hypertension team; informed shared decision
Step 5 — When to suspect secondary hypertension (ESSENTIAL)
A cause is found in ≥10% of hypertensives (more in the young). Consider screening if:
- Age <25, especially very high BP, organ damage, no obesity, no family history
- Spontaneous or diuretic-induced hypokalaemia
- Obesity, snoring, daytime sleepiness (OSA)
- True resistant hypertension
- Malignant hypertension or very high BP (e.g. >180/120)
- Sudden onset or sudden worsening of BP control
- Strong clinical or laboratory clues
These prompt consideration, not mandatory investigation every time. Exclude pseudo-resistance and drug-induced hypertension first. Basic screen = history, examination, basic labs.
Step 6 — The common secondary causes
| Cause | Prevalence | Clues | First test |
|---|
| Primary aldosteronism | 5–10% (up to 20% in resistant) | Hypokalaemia (but >60% normokalaemic) | Aldosterone-to-renin ratio — stop MRAs 4 weeks before; ensure normal K⁺; no sodium restriction |
| Renal parenchymal disease | 5–10% | Often silent | Urine dipstick + eGFR |
| Obstructive sleep apnoea | ~20% (>30% in resistant) | Obesity, resistant or nocturnal hypertension | STOP-Bang or other validated tool; sleep study |
| Renal artery stenosis | 2–5% | Atherosclerosis; women <30 (fibromuscular dysplasia); abdominal bruit; falling eGFR | Renal artery imaging |
| Substance/drug-induced | 2–4% | Drug history | Stop/replace drug |
Uncommon: Cushing's, thyroid disease, coarctation (children/young; arm BP > leg BP, radio-femoral delay), phaeochromocytoma (very rare, variable presentation).
OPTIMAL: choose further tests based on history, exam and basic results; refer to a specialist centre for full secondary workup — it is complex and costly.
Guardrails
- Half of "resistant" hypertension is pseudo-resistance — always exclude it first
- Confirm resistance with home or ambulatory BP before escalating
- Spironolactone is the preferred 4th drug — not a beta-blocker or alpha-blocker
- Hypokalaemia is absent in most primary aldosteronism — normal K⁺ doesn't exclude it
- Stop MRAs 4 weeks before an aldosterone-renin ratio and correct K⁺
- Watch K⁺ and Na⁺ with aldosterone synthase inhibitors, fluid with aprocitentan
- Renal denervation is not first-line — only after optimised drugs, in expert centres, eGFR ≥40
- New drug availability varies — check local approval before recommending
Related MD2SKILL skills
ish-htn-treatment-drug-strategy — the drug ladder up to step 3endo-pa-screen-hypertension, jes-pa-screening-indication — primary aldosteronism workup in detailpheo-screening-strategy — phaeochromocytomaish-htn-emergency — very high BP with organ damage
Source
Stergiou GS, Kario K, Aristizabal D, et al. 2026 International Society of Hypertension Global Hypertension Practice Guidelines. J Hypertens. 2026;44. DOI: 10.1097/HJH.0000000000004451. Sections 7.3–7.4, 9.1–9.3; Tables 11–14; Figure 8.