What is used for resistant hypertension?

Management of Resistant Hypertension

For resistant hypertension, a stepwise approach is recommended, starting with optimizing a three-drug regimen, then adding spironolactone as the fourth agent, followed by beta-blockers, hydralazine, and minoxidil if needed. 1

Definition and Confirmation

• Resistant hypertension is defined as blood pressure that remains above target despite concurrent use of three or more antihypertensive agents of different classes at maximal or maximally tolerated doses, including a diuretic 2
• Before intensifying therapy, exclude pseudoresistance by:
  • Confirming with 24-hour ambulatory blood pressure monitoring to rule out white coat effect 3
  • Assessing medication adherence, which accounts for approximately 50% of apparent treatment resistance 2
  • Ruling out secondary causes of hypertension 1
  • Excluding substance/drug-induced hypertension (NSAIDs, oral contraceptives, stimulants) 2

Treatment Algorithm

Step 1: Optimize Three-Drug Regimen

• Ensure adherence to three antihypertensive agents of different classes at maximum or maximally tolerated doses 1:
  • RAS blocker (ACE inhibitor or ARB)
  • Calcium channel blocker
  • Diuretic (appropriate for kidney function)
• Maximize lifestyle interventions 1:
  • Sodium restriction (<2400 mg/day)
  • Weight loss
  • Regular exercise
  • At least 6 hours of uninterrupted sleep

Step 2: Optimize Diuretic Therapy

• Substitute a thiazide-like diuretic (chlorthalidone or indapamide) for the prior diuretic 1
• These diuretics maintain efficacy down to eGFR of 30 mL/min/1.73m² 1

Step 3: Add Mineralocorticoid Receptor Antagonist

• Add spironolactone (25-50 mg daily) or eplerenone as the fourth agent 1, 3, 4
• Spironolactone has demonstrated superior efficacy in resistant hypertension 2, 5, 6
• Monitor serum potassium and renal function 1-2 weeks after initiation, particularly with existing RAS blockade 2, 7
• If spironolactone is not tolerated due to sexual side effects, eplerenone is an appropriate alternative 4
• Consider amiloride as an alternative if mineralocorticoid receptor antagonists are not tolerated 8, 9

Step 4: Add Beta-Blocker or Alpha-Beta Blocker

• If heart rate is ≥70 beats/min, add beta-blocker (metoprolol succinate, bisoprolol) or combined alpha-beta blocker (labetalol, carvedilol) 1
• If beta-blocker is contraindicated, consider central alpha-agonist (clonidine patch weekly or guanfacine at bedtime) 1
• If these are not tolerated, consider once-daily diltiazem 1

Step 5: Add Vasodilator

• Add hydralazine 25 mg three times daily and titrate upward to maximum dose 1
• In patients with heart failure with reduced ejection fraction, administer hydralazine with isosorbide mononitrate 30 mg daily (max 90 mg daily) 1, 10

Step 6: Consider Minoxidil

• Substitute minoxidil 2.5 mg two to three times daily for hydralazine and titrate upward 1
• If blood pressure still not at target, consider referral to hypertension specialist 1

Evaluation for Secondary Causes

• Screen for primary aldosteronism (even with normal potassium levels) 2
• Evaluate for obstructive sleep apnea 2
• Screen for chronic kidney disease 2
• Consider renal artery stenosis 2
• Assess for endocrine disorders (hypothyroidism, hyperthyroidism, hyperparathyroidism) 1

Common Pitfalls to Avoid

• Failing to confirm true resistant hypertension before escalating therapy 2
• Inadequate diuretic therapy leading to volume overload 2
• Not screening for secondary causes, particularly primary aldosteronism 2
• Overlooking medication non-adherence as a cause of apparent resistance 2
• Using suboptimal medication combinations or inadequate doses 2
• Failing to monitor serum potassium and renal function when using mineralocorticoid receptor antagonists 7