In its first Scientific Statement to focus on this issue, the American Heart Association stresses the need for evaluation that spreads a broad net to identify contributing and secondary causes and treatment options that go beyond the usual antihypertensives.


Uncontrolled hypertension remains a taxing clinical problem. Various surveys find that =50% of patients under treatment achieve target BPs (<140/90 mm Hg; 130/80 for those with diabetes or chronic kidney disease). A substantial proportion (exact number uncertain) suffer from “resistant hypertension,” i.e., their BP remains elevated despite concurrent use of three agents of different classes.

In its first Scientific Statement to focus on this issue, the American Heart Association (AHA) stresses the need for evaluation that spreads a broad net to identify contributing and secondary causes and treatment options that go beyond the usual antihypertensives.

“There's been growing interest in the subject of resistant hypertension, both clinically and from a research perspective,” says David A. Calhoun, MD, professor of medicine in the vascular biology and hypertension program at The University of Alabama at Birmingham and chair of the committee that produced the document. “General clinicians as well as specialists should recognize that these patients represent a subgroup deserving of special consideration.”

Under the rubric of “resistant hypertension,” the AHA document includes BP that has been reduced to goal levels with four or more drugs. “Maintaining control with fewer medications would translate to improved quality of life for the patient,” and the Statement's protocol might uncover reversible factors to make that possible, Dr. Calhoun said.

Is it really resistant?

The first priority in evaluating patients with suspected resistant hypertension (see table below) is to rule out “pseudoresistance,” the misleading appearance of inadequate response. This is most often due to problems with technique (e.g., too small a cuff or failure to allow the patient to sit quietly for several minutes prior to testing) or to poor treatment adherence. An estimated 40% of hypertensive patients discontinue medication during their first year.





Pseudoresistance may also represent the “white coat effect.” Home monitoring that produces consistently lower readings, indications of overtreatment (such as orthostatic symptoms), and the lack of target organ damage point to this possibility. To confirm white coat hypertension definitively, the authors recommend 24-hour ambulatory monitoring (mean values should be <135/85). 

Contributing factors

“Resistant hypertension is almost always multifactorial,” Dr. Calhoun says. “And lifestyle factors are almost always contributory.” Although these factors have not been evaluated in the resistant population per se, being overweight is generally associated with more severe hypertension and the need for more medications, and weight loss is associated with  reductions in BP and drug burden. 

Salt restriction has likewise been shown to benefit hypertensive patients, and although its efficacy has not yet been demonstrated in this subgroup, “dietary salt restriction, ideally to sodium <100 mEq/24 hours, should be recommended to all patients with resistant hypertension,” assert the authors.

Because excess alcohol is known both to elevate BP and compromise its control, men should consume no more than two standard drinks daily and women no more than one. The BP-lowering effect of physical activity appears modest but real, and the Statement recommends that patients be encouraged to exercise at least 30 minutes most days of the week. There is also evidence to support a diet rich in fruits and vegetables and low in saturated fats.

Medications that interfere with BP control should be withdrawn when possible or reduced to the lowest effective dose. The most frequent offenders are nonnarcotic analgesics, particularly nonsteroidal anti-inflammatory drugs, which have been shown to increase BP modestly (about 5.0 mm Hg) and to blunt the effect of certain antihypertensive agents (diuretics, ACE inhibitors, angiotensin receptor blockers [ARBs], and beta blockers).

Sympathomimetic compounds (e.g., in decongestants and diet pills), oral contraceptives, psychostimulants, and modafinil (Provigil) may also worsen BP control, as may herbal preparations (e.g., ephedra, ma huang) and licorice. Glucocorticoids can increase BP significantly.

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 physicians 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.

Among the 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. The table below 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). It is available online at hyper.ahajournals.org/cgi/reprint/HYPERTENSIONAHA.108.189141v1, accessed April 21, 2009.

Mr. Sherman is a medical writer in New York City.