Secondary causes of resistant hypertension
Conditions complicating BP control must be identified and addressed. Among the more common secondary causes of resistant hypertension are obstructive sleep apnea, chronic kidney disease, primary aldosteronism, and renal artery stenosis.
Primary-care clinicians should be aware of indications for further investigation: Snoring or excessive daytime sleepiness suggests possible sleep apnea; known atherosclerotic disease and worsening renal function may indicate renal artery stenosis.
Primary aldosteronism is far more common than had been previously thought, according to recent research. (Various studies have found the prevalence to be 6.1% among hypertensive patients, 13% in patients whose hypertension is severe, and 20%-23% in those with resistant hypertension.) The general biochemical evaluation recommended by the authors includes determination of the aldosterone-to-renin ratio to screen for primary aldosteronism.
Less common secondary causes of resistant hypertension are pheochromocytoma (suggested by episodic headaches, palpitations, and sweating), Cushing syndrome, and aortic coarctation.
Pharmacotherapy
The authors note that in patients with resistant hypertension referred to specialized clinics, diuretics are often underused, and BP is most effectively reduced by increasing the diuretic dosage, adding a diuretic, or switching diuretic class. Based on evidence of superior efficacy, chlorthalidone is recommended over hydrochlorothiazide for resistant hypertension.
Combination regimens should include agents with different mechanisms of action. “A triple regimen of an ACE inhibitor or ARB, calcium channel blocker, and thiazide diuretic is effective and generally well-tolerated,” the authors say.
For patients who have heart failure or coronary heart disease, combined alpha-beta antagonists appear to be particularly effective antihypertensives; loop diuretics are indicated for those with chronic kidney disease.
In addition to standard hypertension drugs, clinicians should consider a mineralocorticoid receptor agonist, such as spironolactone or amiloride; studies have shown significant benefits (e.g., BP reductions of 25/12 mm Hg) for hypertension that was poorly controlled on a multidrug regimen. 
There is evidence of better outcomes when patients take at least one antihypertensive at bedtime. “It may be that twice-daily dosing of nondiuretic BP medications will improve control rates,” the authors say, although reduced adherence is a risk. Table 2 presents a list of treatment options—both pharmacologic and nonpharmacologic.
When to refer
Referral to a hypertension specialist or specialized clinic might be considered at any point and is clearly indicated if BP remains elevated despite six months of treatment.
Otherwise, when to refer is largely a matter of individual preference and experience. “Some primary-care clinicians will feel comfortable going forward after identifying resistant hypertension; others will refer early on,” Dr. Calhoun says. For many, referral may be indicated when secondary causes of hypertension are suspected or diagnosed, or when complex pharmacotherapy regimens (perhaps involving less familiar drugs, like mineralocorticoid receptor antagonists) are needed.
Resistant Hypertension: Diagnosis, Evaluation and Treatment. A Scientific Statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research was published in Hypertension (2008;51:1403-1419).
