From the Guidelines
Resistant hypertension workup should begin with confirming true resistance by ensuring proper blood pressure measurement technique and ruling out white coat hypertension through ambulatory or home blood pressure monitoring, as recommended by the 2024 ESC guidelines for the management of elevated blood pressure and hypertension 1. The evaluation should include a comprehensive medical history, physical examination, and laboratory tests including basic metabolic panel, urinalysis, lipid profile, and hemoglobin A1c. Key aspects to consider in the workup include:
- Secondary causes of hypertension such as obstructive sleep apnea, primary aldosteronism (check aldosterone-to-renin ratio), renal artery stenosis (consider duplex ultrasound or CT angiography), pheochromocytoma (measure plasma metanephrines), and Cushing's syndrome (perform overnight dexamethasone suppression test) 1.
- Medications that can elevate blood pressure, including NSAIDs, oral contraceptives, sympathomimetics, and certain antidepressants.
- Lifestyle factors such as excessive sodium intake, alcohol consumption, physical inactivity, and obesity. Treatment optimization involves ensuring the patient is on a three-drug regimen that includes a diuretic, an ACE inhibitor or ARB, and a calcium channel blocker. If blood pressure remains uncontrolled, adding a mineralocorticoid receptor antagonist like spironolactone (25-50mg daily) is often effective as a fourth agent, as supported by the 2024 ESC guidelines 1. Additionally, the 2020 International Society of Hypertension global hypertension practice guidelines suggest considering screening patients for secondary causes, optimizing the current treatment regimen, and adding a low dose of spironolactone as the 4th line agent in those whose serum potassium is <4.5 mmol/L and whose eGFR is >45 ml/min/1.73m2 to achieve BP targets 1.
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 2.
Diagnosis of Resistant Hypertension
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 2.
Management of Resistant Hypertension
The key management points of this condition 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 2
- Rationalisation of current treatment, including single pill combination treatment where antihypertensive drugs should be provided at the maximum tolerated dose 2
- Replacement of current drugs with a more appropriate and less difficult treatment regimen based on the patient's age, ethnicity, comorbidities and risk of drug-drug interactions 2
- 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 2
- Alternatives to spironolactone include amiloride, doxazosin, eplerenone, clonidine and beta-blockers, as well as any other antihypertensive drugs not already in use 2
Treatment Options
Combination therapy including a diuretic, a long-acting calcium channel blocker, an angiotensin-converting enzyme inhibitor, a beta blocker, and a mineralocorticoid receptor antagonist where warranted is the classic regimen for patients with treatment-resistant hypertension 3. Mineralocorticoid receptor antagonists like spironolactone or eplerenone have been shown to be efficacious in patients with RHTN, heart failure, chronic kidney disease, and primary aldosteronism 3. Moderate doses of an ARB/CCB combination with HCTZ reduced blood pressure more effectively than the maximal dose of an ARB with HCTZ 4. ACE inhibitors remain associated with cough and a very low risk of angioedema and fatalities, whereas ARBs have equal outcome efficacy but fewer adverse events 5. The fixed combination ramipril/amlodipine represents a first choice therapy for hypertension, considering also the availability of studies that demonstrate its effectiveness on intermediate endpoints associated with high tolerability 6.
Secondary Causes of Hypertension
Secondary causes of hypertension, including obstructive sleep apnea, primary aldosteronism, renovascular disease, are common in patients with RHTN and often coexist in the same patient 3.
New Approaches
New approaches under research are selective non-steroidal mineralocorticoid receptor antagonists such as finerenone, esaxerenone and ocedurenone, selective aldosterone synthase inhibitors such as baxdrostat, and dual endothelin antagonist aprocitentan 2. Novel interventional therapies, including baroreflex activation and renal denervation, have shown that both of these methods may be used to lower blood pressure safely, thereby providing exciting and promising new options to treat RHTN 3.