What is the appropriate workup and treatment for resistant hypertension (high blood pressure that is difficult to control)?

From the Guidelines

Resistant hypertension should be managed with a combination of lifestyle modifications and pharmacological treatments, starting with reinforcement of lifestyle measures, especially sodium restriction, and addition of low-dose spironolactone to existing treatment, as recommended by the 2024 ESC guidelines 1. The workup for resistant hypertension should include screening for secondary causes such as primary aldosteronism, renal artery stenosis, obstructive sleep apnea, pheochromocytoma, and Cushing's syndrome. Some key points to consider in the management of resistant hypertension include:

• Confirming true resistant hypertension by ensuring proper blood pressure measurement technique and ruling out white coat hypertension with 24-hour ambulatory monitoring 1
• Optimizing the current antihypertensive regimen, which should include a diuretic, an ACE inhibitor or ARB, and a calcium channel blocker
• Adding a mineralocorticoid receptor antagonist like spironolactone as a fourth agent if blood pressure remains uncontrolled
• Considering alternative fourth-line options such as beta-blockers, alpha-blockers, or centrally-acting agents
• Assessing and addressing medication adherence, as non-adherence is common
• Implementing lifestyle modifications, including sodium restriction, weight loss, regular exercise, limited alcohol consumption, and a DASH diet According to the 2024 ESC guidelines, the addition of spironolactone to existing treatment should be considered in patients with resistant hypertension and uncontrolled BP despite use of first-line BP-lowering therapies 1. Additionally, treatment with eplerenone instead of spironolactone, or the addition of a beta-blocker if not already indicated, and, next, a centrally acting BP-lowering medication, an alpha-blocker, or hydralazine, or a potassium-sparing diuretic should be considered in patients with resistant hypertension in whom spironolactone is not effective or tolerated 1. Catheter-based renal denervation may be considered for resistant hypertension patients who have BP that is uncontrolled despite a three BP-lowering drug combination, and who express a preference to undergo renal denervation after a shared risk-benefit discussion and multidisciplinary assessment 1.

From the FDA Drug Label

Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC)

The treatment of resistant hypertension may involve the use of multiple antihypertensive agents, such as spironolactone 2, amlodipine 3, and lisinopril 4.

• Key considerations in the treatment of resistant hypertension include:
  • The use of combination therapy to achieve blood pressure goals
  • Comprehensive cardiovascular risk management, including lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake
  • Guideline-directed therapy, as recommended by organizations such as the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) It is essential to consult published guidelines for specific advice on goals and management of resistant hypertension.

From the Research

Resistant Hypertension Workup

• Resistant hypertension is a condition where blood pressure levels remain elevated above target despite changes in lifestyle and concurrent use of at least three antihypertensive agents, including a long-acting calcium channel blocker (CCB), a blocker of the renin-angiotensin system (ACE inhibitor or angiotensin receptor blocker) and a diuretic 5.
• To be diagnosed as resistant hypertension, maintaining adherence to therapy is required along with confirmation of blood pressure levels above target by out-of-office blood pressure measurements and exclusion of secondary causes of hypertension 5.
• The evaluation of suspected secondary resistant hypertension can be categorized into pseudoresistant hypertension and true resistant hypertension, with causes of true resistant hypertension including obstructive sleep apnea, primary aldosteronism, and renal artery stenosis 6.

Treatment of Resistant Hypertension

• The key management points of resistant hypertension include lifestyle changes such as reduced sodium and alcohol intake, regular physical activity, weight loss and discontinuation of substances that can interfere with blood pressure control 5.
• Current treatment should be rationalised, including single pill combination treatment where antihypertensive drugs should be provided at the maximum tolerated dose 5.
• The fourth line of treatment for patients with resistant hypertension should include mineralocorticoid receptor antagonists such as spironolactone, as demonstrated in the PATHWAY-2 trial and meta-analyses 5.
• Alternatives to spironolactone include amiloride, doxazosin, eplerenone, clonidine and beta-blockers, as well as any other antihypertensive drugs not already in use 5.
• Therapeutic lifestyle changes, such as being active, weight-loss, consuming a diet rich in fruits and vegetables, and sodium below the recommended threshold, can be effective in lowering blood pressure in patients with resistant hypertension 7.

Pharmacologic Treatment

• First-line drug therapy for hypertension consists of a thiazide or thiazidelike diuretic, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and a calcium channel blocker, which should be titrated according to office and home SBP/DBP levels to achieve target blood pressure 8.
• Randomized clinical trials have established the efficacy of BP lowering to reduce the risk of CVD morbidity and mortality, with an SBP reduction of 10 mm Hg decreasing risk of CVD events by approximately 20% to 30% 8.
• New approaches under research include selective non-steroidal mineralocorticoid receptor antagonists, selective aldosterone synthase inhibitors, and dual endothelin antagonist aprocitentan 5.