What is the appropriate work‑up for resistant hypertension?

Workup for Resistant Hypertension

Confirm True Resistant Hypertension First

Perform 24-hour ambulatory blood pressure monitoring (ABPM) as the gold standard to exclude white-coat hypertension, which accounts for approximately 50% of apparent resistant cases. 1, 2 If ABPM is unavailable, use validated home blood pressure monitoring as an alternative. 1

• Verify proper office BP measurement technique using correctly sized cuff and correct patient positioning to avoid pseudoresistance. 3, 1
• Confirm the patient is taking at least three antihypertensive medications at maximum tolerated doses from different classes, including a diuretic (specifically a renin-angiotensin system blocker, long-acting dihydropyridine calcium channel blocker, and appropriate diuretic). 2
• Assess medication adherence through direct questioning, pill counts, or pharmacy records, as non-adherence is the most common cause of apparent treatment resistance. 3, 1

Baseline Laboratory Evaluation

Obtain the following baseline labs in all patients:

• Serum potassium and estimated glomerular filtration rate (eGFR) to assess renal function and guide diuretic selection. 1, 2
• Thyroid-stimulating hormone (TSH) to evaluate for thyroid dysfunction. 1
• Plasma aldosterone concentration (PAC) and plasma renin activity (PRA) to screen for primary aldosteronism, even when potassium is normal, particularly in patients younger than 30 years. 1, 2

Screen for Secondary Causes

Primary aldosteronism is the most important secondary cause to identify:

• Screen with PAC and PRA ratio even with normal potassium levels, as hypokalemia is present in only a minority of cases. 2

Obstructive sleep apnea is commonly present in resistant hypertension:

• Evaluate using Berlin Questionnaire or Epworth Sleepiness Score, confirming with polysomnography if suspected. 1

Renal artery stenosis:

• Perform kidney ultrasound followed by renal artery imaging (CT angiography or MR angiography) if clinically indicated, particularly in patients with abrupt onset of severe hypertension, flash pulmonary edema, or progressive renal insufficiency. 1

Chronic kidney disease:

• Baseline serum creatinine and eGFR calculation are essential, as CKD is both a cause and consequence of resistant hypertension. 2

Identify Contributing Factors

Review and discontinue or minimize interfering substances:

• NSAIDs (including over-the-counter ibuprofen and naproxen)
• Stimulants (amphetamines, cocaine, energy drinks)
• Oral contraceptives
• Certain antidepressants (SNRIs, MAOIs)
• Decongestants (pseudoephedrine, phenylephrine)
• Excessive alcohol intake (>2 drinks/day for men, >1 drink/day for women) 2

Assess Lifestyle Factors

Document the following modifiable factors:

• Dietary sodium intake: Quantify current intake and assess feasibility of restriction to <2400 mg/day (ideally <1500 mg/day). 1
• Body mass index and weight: Obesity significantly contributes to treatment resistance. 1
• Physical activity level: Sedentary lifestyle worsens BP control. 1

Determine Need for Specialist Referral

Refer to a hypertension specialist if blood pressure remains uncontrolled (>130/80 mmHg) after 6 months of optimized three-drug therapy. 4, 2 Hypertension specialists achieve BP control in approximately 52-53% of resistant cases, with average reductions of 18/9 mmHg at 1-year follow-up. 4, 2

Refer to appropriate subspecialists if specific secondary causes are identified:

• Endocrinology for primary aldosteronism or other endocrine disorders
• Nephrology for renovascular disease or advanced CKD
• Sleep medicine for obstructive sleep apnea 4

Common Pitfalls to Avoid

• Do not skip ambulatory or home BP monitoring, as white-coat hypertension accounts for roughly half of apparent resistant cases. 1, 2
• Do not assume normal potassium excludes primary aldosteronism—most patients with primary aldosteronism are normokalemic. 1
• Do not overlook medication adherence assessment—non-adherence is the most common cause of pseudoresistance. 3
• Do not fail to verify that the current regimen includes a thiazide-like diuretic (chlorthalidone or indapamide) rather than standard hydrochlorothiazide, as thiazide-like agents are significantly more effective. 3, 1