Resistant hypertension: Diagnostic strategies and management
ABSTRACTBlood pressure that remains above target levels despite drug therapy is an increasingly common problem. The evaluation of resistant hypertension includes confirming blood pressure measurements with an automated device that works without the clinician present and with 24-hour ambulatory monitoring; assessing for target-organ damage; and determining if kidney disease is present or if the hypertension is secondary to another condition. The goal of management should be to optimize drug therapy by using different classes of appropriate drugs.
KEY POINTS
- Resistant hypertension is arbitrarily divided into two categories: apparent resistance (pseudoresistant hypertension) and true resistance. Apparent resistance is much more common.
- Common causes of true resistant hypertension are volume overload, excessive alcohol use, some drugs (eg, nonsteroidal anti-inflammatory drugs), and some over-the-counter supplements.
- Volume overload commonly results from excess sodium intake, kidney disease, or a counterregulatory response to arterial vasodilation.
- To address volume overload, an appropriate diuretic at an adequate dosage is a cornerstone of therapy, along with potassium supplementation.
- Hospitalization may be needed to monitor drug intake if poor compliance is suspected.
Many factors can contribute to true resistance
Many cases of resistant hypertension are drug-induced, particularly in patients taking a nonsteroidal anti-inflammatory drug or a cyclooxygenase II inhibitor. Use of ginseng, ma huang, and bitter lemon should also be suspected. Drugs or herbal preparations contributing to high blood pressure should be discontinued or minimized.
Alcohol intake in excess of two drinks (1 oz of alcohol) per day for men and half that amount for women can also contribute to hypertension.
Volume overload is common and has many causes, including a compensatory response to vasodilators, excessive salt intake, or an undetected reduction in the glomerular filtration rate causing retention of salt and water.
Drug considerations
A common cause of apparent resistant hypertension is physicians not following blood pressure treatment guidelines by not increasing the dosage when needed or by prescribing inappropriate drug combinations.
We commonly see furosemide (Lasix) being misused, ie, being prescribed once daily for hypertension. (It has a shorter duration of action than thiazide diuretics, the usual class of diuretics used for hypertension.)
For a patient who is already on many medications but whose hypertension is not responding, the first step should be to give a diuretic of an appropriate class in an appropriate dosage.
Diuretics are often inappropriately stopped if a patient develops hypokalemia. Potassium supplementation should always be an adjunct to diuretic therapy. Potassium itself is a potent vasodilator and, given as a supplement, has been shown to reduce stroke risk in rats.
The combination of an angiotensin receptor blocker and an angiotensin-converting enzyme inhibitor should not be used for patients with true resistant hypertension. The direct renin inhibitor aliskiren (Tekturna) should not be used in combination with these drugs, and the combination of aliskiren and valsartan (Valturna) has now been taken off the market.
Spironolactone (Aldactone) is sometimes used for resistant hypertension in the belief that in some cases primary aldosteronism is the underlying cause. A study in 1,400 participants confirms that it lowers blood pressure,9 but the reason is unclear: the blood pressure response was unrelated to levels of renin, angiotensin, or the plasma aldosterone-to-renin ratio.
Identify secondary causes of hypertension
Patients should be evaluated for kidney disease, which is the most common secondary medical reason for resistant hypertension. For patients with poor renal function (estimated glomerular filtration rate < 50 mL/minute), hydrochlorothiazide is not effective against hypertension, but chlorthalidone is. In addition, patients with poor renal function should be given loop diuretics such as furosemide two or three times daily, or the long-acting drug torsemide (Demadex) should be used instead.
Genetic variation can cause different rates of metabolism of drugs, contributing to resistant hypertension. Certain people metabolize hydralazine very fast, making it less effective. The same is true for some beta-blockers.
Obesity and diabetes can also contribute to resistant hypertension.
Ancillary neurohumoral studies are occasionally indicated to rule out identifiable causes of secondary hypertension that may be correctable. There are many identifiable causes of hypertension, but detailing each is beyond the scope of this article.
Patients should be tested for thyroid disease. Hypothyroidism can cause high blood pressure, although usually diastolic rather than systolic hypertension. Hyperthyroidism can cause marked systolic hypertension.
Table 1 provides a step-by-step guide for evaluating and managing patients with resistant hypertension.
EXPERIMENTAL DRUG THERAPY
Endothelin receptor antagonists are currently under investigation for the treatment of resistant hypertension. The protein endothelin-1 (ET-1) is a potent vasoconstrictor (30–50 times more potent than angiotensin II and norepinephrine) and has a long duration of action. ET-1 binds to two receptors with opposing effects: ET-A promotes vasoconstriction, and ET-B promotes vasodilation and clears ET-1.
Darusentan, a selective blocker of ET-A, was tested in the phase III DORADO trial, which was discontinued because the initial results did not meet primary outcome measures. Initial findings had indicated that it might not be as useful as hoped. Side effects included headache, flushing, and edema.
