What Next for Patients With Resistant Hypertension?

Q: Is there a role for aldosterone antagonists in resistant hypertension?

A: Resistant hypertension is defined as blood pressure (BP) that is persistently higher than 140/90 mm Hg despite treatment with at least 3 antihypertensive agents of different classes, one of which is a diuretic. Hypertension that requires 4 or more medications for control-with or without a diuretic in the regimen-is considered highly resistant. In terms of diagnosis and therapy, hypertension controlled with 4 or more agents differs from hypertension controlled with 3 agents. The current definition of resistant hypertension excludes “resistance” as long as BP is controlled, even if more than 3 drugs are required. Obviously, a patient who requires 5 or 6 drugs for BP to be controlled below 140/90 mm Hg represents a greater degree of resistance than the patient whose BP is controlled with 3 drugs. The ability to control BP with multiple drugs will also be significantly affected in the patient who cannot tolerate an oral diuretic.

A systematic approach to the patient with resistant hypertension is both cost-effective and rewarding because the evaluation will probably reveal the cause. Initial considerations include lack of adherence, inappropriate treatment, drug-drug interactions, volume overload, and white-coat hypertension. Once these have been ruled out, identification of potential secondary causes of hypertension becomes imperative. Sleep apnea and chronic kidney disease are the most common causes of secondary hypertension; however, primary hyperaldosteronism (defined by strict diagnostic criteria) occurs in 20% to 22% of patients who have resistant hypertension.^1,2

Moreover, clinical experience has shown that other patients with resistant hypertension have suppressed reninlevels and normal or high-normal aldosterone levels that are considered undesirable in the setting of resistant hypertension and often excessive dietary sodium intake. The causes of this phenomenon are not clearly understood.

Nishizaka and colleagues³ have reported that more than 75% of the patients whom they see with resistant hypertension have low renin levels despite treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and diuretics, all of which should increase plasma renin activity. Thus, normal or high-normal plasma aldosterone levels in this group of patients are excessive, and aldosterone blockade becomes a therapeutic option.

In patients with resistant hypertension, spironolactone, in dosages as low as 12.5 to 50 mg/d, added to a regimen of 3 or more antihypertensive drugs, can produce significant additional reductions in BP without serious adverse reactions. These results have been observed in both African American and white patients.⁴

Although spironolactone is generally well tolerated as adjunctive therapy, worsening of renal insufficiency has occurred in patients who have preexisting renal disease; this effect can usually be reversed by down-titration or discontinuation of the drug. Hyperkalemia sometimes develops in patients with renal disease or in those taking ACE inhibitors or ARBs. Another common adverse effect of spironolactone is breast tenderness, which occurs in about 10% of men. Limited experience with a newer aldosterone antagonist, eplerenone, has suggested that its efficacyis similar to that of spironolactone, independent of plasma renin or plasma aldosterone concentrations.^4,5