Resistant Hypertension: Workup & Triple Therapy

“Resistant” hypertension is not just “stubborn blood pressure.” First confirm the diagnosis, remove measurement and adherence errors, hunt down secondary causes (they’re common), then apply evidence-based drug sequencing with tight safety monitoring.

Definitions (start precise)

• Resistant hypertension (RH): Office BP above goal despite 3 antihypertensives at optimal doses, ideally including a diuretic; or BP controlled but requiring ≥4 agents.
• Refractory hypertension: Uncontrolled despite ≥5 agents including a diuretic and a mineralocorticoid receptor antagonist (MRA).
• White-coat & masked hypertension: Use home or ambulatory BP monitoring (ABPM) to uncover them.

Step 1 — Confirm it’s real (not pseudo-resistance)

• Measurement: proper cuff size, seated 5 minutes, back/feet supported, arm at heart level, no caffeine/exercise/smoking for 30 min, take 2–3 readings and average.
• Home BP: 7-day log (discard day 1; average morning + evening). Consider ABPM if available.
• Adherence & access: ask nonjudgmentally; simplify to once-daily combos when possible; address side effects and cost.
• Drugs that raise BP: NSAIDs, oral decongestants, stimulants, some antidepressants (SNRIs), oral contraceptives, calcineurin inhibitors, EPO, high-dose steroids, licorice/supplements.
• Alcohol, sodium, and sleep: high sodium, heavy alcohol, and untreated OSA commonly sabotage control.

Step 2 — Screen for secondary causes (targeted, high-yield)

• Primary aldosteronism: think hypokalemia, adrenal nodule, or resistant HTN. Check plasma aldosterone/renin ratio (AM, seated). Correct K⁺ first and interpret with meds in mind; confirmatory testing per protocol.
• Obstructive sleep apnea (OSA): loud snoring, witnessed apneas, daytime sleepiness, large neck circumference → refer for sleep study; CPAP can meaningfully reduce BP in adherent users.
• Renal parenchymal disease: check eGFR, urinalysis (protein/hematuria), renal ultrasound if indicated.
• Renal artery stenosis: consider with flash pulmonary edema, asymmetric kidneys, abdominal bruit, or abrupt creatinine rise after ACEi/ARB; evaluate with duplex US, CTA, or MRA.
• Endocrine: pheochromocytoma/paraganglioma (paroxysmal headache, palpitations, sweating—plasma metanephrines), Cushing’s (features of hypercortisolism), thyroid (TSH), hyperparathyroidism (Ca²⁺).
• Coarctation (younger adults): arm–leg BP gradient, diminished femoral pulses → imaging.

Step 3 — The evidence-based regimen (triple therapy core)

When no red flags and after basics above, build the following:

1. ACE inhibitor or ARB (choose one). Examples: lisinopril, valsartan.
2. Long-acting dihydropyridine CCB (amlodipine or equivalent).
3. Thiazide-like diuretic (prefer chlorthalidone or indapamide over HCTZ for potency/duration).

Reassess in 2–4 weeks with home BP averages. Titrate to maximally tolerated doses. In CKD with eGFR <30, loop diuretics outperform thiazides; chlorthalidone can still work at lower eGFR but monitor closely.

Step 4 — Add a mineralocorticoid receptor antagonist (MRA)

• Spironolactone 12.5–25 mg daily (up to 50 mg) is the preferred 4th agent in true RH.
• Eplerenone if gynecomastia or sexual side effects (BID dosing typically needed).
• Safety: check K⁺/creatinine 1–2 weeks after starting or dose changes; avoid if baseline K⁺ high or advanced CKD without close monitoring.

Step 5 — If still uncontrolled (individualize)

• Beta-blocker (especially with CAD, tachyarrhythmias) — e.g., bisoprolol, carvedilol.
• Central agents (clonidine patch/oral) for adherence or refractory cases.
• Vasodilators (hydralazine; minoxidil with loop diuretic + beta-blocker if used).
• Consider SGLT2 inhibitors in patients with diabetes/CKD/heart failure for cardiorenal benefit and modest BP reduction.
• Device therapy (renal denervation) is emerging—availability, selection, and outcomes vary by region; reserve for specialized centers.

Lifestyle therapy that actually moves numbers

• Sodium: target ~2 g/day (5 g salt). Restaurant/processed foods are the main culprits.
• Weight: even 5–10% loss lowers BP materially; pair resistance + aerobic training.
• Alcohol: reduce to ≤2 drinks/day (men) or ≤1 (women), fewer is better.
• Sleep: diagnose and treat OSA; regular sleep schedule.
• Medication timing: once-daily AM vs PM can be individualized; prioritize adherence and side-effect profile.

Targets & monitoring

• Many adults: <130/80 mmHg if tolerated; individualize for frailty and comorbidity.
• Labs after changes in ACEi/ARB/MRA/diuretics: BMP in 1–2 weeks; then every 3–6 months when stable.
• Track home BP; bring device to clinic to validate against manual reading.

Special populations

• CKD: RAAS blockade beneficial; thiazide-like → loop with low eGFR; careful K⁺ monitoring with MRA.
• Black patients: DHP-CCB + thiazide-like are particularly effective early; RAAS blockade still indicated with CKD/albuminuria or diabetes.
• Pregnancy: avoid ACEi/ARB/MRA. Use labetalol, nifedipine ER, or methyldopa per obstetric guidance.
• Older adults/frailty: aim for safety—orthostatic checks, fall risk, and conservative titration.

Red flags (don’t miss)

• Severe BP with acute target-organ damage → treat as hypertensive emergency in monitored care.
• Rapid creatinine rise >30% after ACEi/ARB start, refractory hypokalemia (think aldosteronism), paroxysmal spells (think pheo), or secondary causes suggested by history/exam.

Patient FAQs

“Why am I on so many pills?” Each class targets a different pathway; smaller doses of multiple drugs lower BP better with fewer side effects than one big dose.

“Can salt really be the problem?” Yes—hidden sodium is a top driver of “resistance.” Cooking at home and label reading drop BP measurably.

References & Notes

Practical sequence: confirm true resistance → fix basics → screen secondary causes → triple therapy (ACEi/ARB + DHP-CCB + thiazide-like) → add MRA → individualized add-ons. Local protocols vary—follow institutional guidance. Educational only.