What is the workup for resistant hypertension?

From the Guidelines

The workup for resistant hypertension should begin with confirming true resistance and optimizing treatment, including the addition of spironolactone to existing treatment, as recommended by the 2024 ESC guidelines 1. The diagnosis of resistant hypertension requires careful evaluation to rule out pseudoresistance due to factors such as white coat hypertension or non-adherence to medication.

Initial Steps

• Confirming true resistance by ensuring proper blood pressure measurement technique and ruling out white coat hypertension through ambulatory or home blood pressure monitoring.
• Assessing medication adherence, as non-adherence is a common cause of apparent resistance.
• A thorough medication review is essential to identify drugs that may elevate blood pressure, such as NSAIDs, oral contraceptives, decongestants, and certain antidepressants.

Laboratory Evaluation

• Laboratory evaluation should include basic metabolic panel, urinalysis, lipid profile, fasting glucose, and thyroid function tests.
• Secondary causes of hypertension must be investigated, particularly primary aldosteronism (check aldosterone-to-renin ratio), chronic kidney disease (assess GFR and urine albumin-to-creatinine ratio), renal artery stenosis (consider duplex ultrasound or CT angiography in high-risk patients), pheochromocytoma (measure plasma metanephrines), and obstructive sleep apnea (screen with questionnaires and refer for sleep study if indicated).

Treatment Optimization

• Treatment optimization involves ensuring the patient is on a three-drug regimen including a thiazide diuretic, an ACE inhibitor or ARB, and a calcium channel blocker.
• The addition of spironolactone to existing treatment is recommended for patients with resistant hypertension and uncontrolled BP despite use of first-line BP-lowering therapies 1.
• Other options include beta-blockers, alpha-blockers, or centrally acting agents.
• Lifestyle modifications remain crucial, including sodium restriction, weight loss, regular physical activity, limited alcohol consumption, and adoption of the DASH diet. According to the 2024 ESC guidelines, the recommended treatment of resistant hypertension includes reinforcement of lifestyle measures, especially sodium restriction, and the addition of low-dose spironolactone to existing treatment 1. In patients with resistant hypertension in whom spironolactone is not effective or tolerated, 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 1. The 2024 ESC guidelines also recommend upfront low-dose combination therapy for the treatment of hypertension, with the potential advantages of fewer side effects and swifter BP control being important for long-term adherence 1. However, the choice of treatment should be individualized based on the patient's specific needs and circumstances. Overall, the management of resistant hypertension requires a comprehensive approach that includes careful evaluation, optimization of treatment, and lifestyle modifications to improve blood pressure control and reduce the risk of cardiovascular disease.

From the FDA Drug Label

Initiate therapy in gradually increasing dosages; adjust according to individual response. In a few resistant patients, up to 300 mg of hydrALAZINE hydrochloride tablets daily may be required for a significant antihypertensive effect. In such cases, a lower dosage of hydrALAZINE hydrochloride tablets combined with a thiazide and/or reserpine or a beta blocker may be considered However, when combining therapy, individual titration is essential to ensure the lowest possible therapeutic dose of each drug.

The workup for resistant hypertension is not directly addressed in the provided drug label. However, for patients with resistant hypertension, the label suggests considering a combination of hydralazine with a thiazide and/or reserpine or a beta blocker, with individual titration to ensure the lowest possible therapeutic dose of each drug 2.

From the Research

Definition and Diagnosis of Resistant Hypertension

• Resistant hypertension is defined as uncontrolled blood pressure despite the use of at least three antihypertensive agents of different classes, including a diuretic, at maximal or maximally tolerated doses 3, 4, 5, 6, 7.
• The diagnosis of resistant hypertension requires the exclusion of non-adherence, "white coat effect", and incorrect blood pressure measurement 5, 6, 7.
• Out-of-office blood pressure measurements, ideally using 24-hour ambulatory blood pressure monitoring, should be used to confirm the diagnosis 4, 6.

Evaluation and Management of Resistant Hypertension

• Evaluation of suspected resistant hypertension starts with confirming adherence to the drug regimen and ruling out secondary causes of hypertension, such as obstructive sleep apnea, primary aldosteronism, and renovascular disease 3, 4, 5, 6.
• Lifestyle modifications, including exercise, dietary sodium restriction, weight loss, and discontinuation of substances that can interfere with blood pressure control, are recommended 3, 4, 5, 6.
• The treatment of resistant hypertension typically includes a combination of lifestyle adjustments, pharmacologic treatment, and interventional treatment 3, 4, 5, 6, 7.
• Pharmacologic treatment may include a diuretic, a long-acting calcium channel blocker, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and a mineralocorticoid receptor antagonist such as spironolactone 3, 4, 5, 6, 7.

Treatment Options for Resistant Hypertension

• Mineralocorticoid receptor antagonists, such as spironolactone or eplerenone, have been shown to be efficacious in patients with resistant hypertension, heart failure, chronic kidney disease, and primary aldosteronism 3, 4, 5, 7.
• Other treatment options may include beta blockers, long-acting nondihydropyridine calcium channel blockers, clonidine, or guanfacine 4, 6.
• Novel interventional therapies, including baroreflex activation and renal denervation, have shown promise in lowering blood pressure in patients with resistant hypertension 3.
• Referral to a hypertension subspecialist should be considered when blood pressure is not controlled despite adherence to a four-drug regimen 6.