Refractory Hypertension:10 Steps to Uncover the Cause

January 1, 2007

Q:How can I accurately determine when a patient’s hypertension isresistant to treatment-and what is the best approach to theevaluation?

Q: How can I accurately determine when a patient’s hypertension is resistant to treatment-and what is the best approach to the evaluation?

Fewer than 30% of Americans who are being treated for hypertension have blood pressures (BPs) that are controlled to the recommended goal of 140/90 mm Hg. Consequently, increasing numbers of patients with resistant or refractory hypertension are being referred to hypertension specialists. Most are not truly resistant to treatment: a systematic evaluation can provide a cost-effective means of identifying causative factors in upwards of 95% of these patients.

According to the sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure, hypertension can be considered resistant if BP cannot be reduced to below 140/90 mm Hg despite adherence to an adequate and appropriate 3-drug regimen that includes a diuretic, with all 3 agents prescribed in near maximum recommended doses.1 For older patients with isolated systolic hypertension, resistance can be defined as failure to reduce systolic BP below 160 mm Hg with a similar regimen.1 Clinical trials in systolic hypertension have suggested, however, that a lower level of systolic BP (probably 150 mm Hg) would be more appropriate.

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Let me suggest a sequential, step-wise evaluation (Table). The first 6 steps can be accomplished in your office.2

1. Consider office hypertension and, in older persons, pseudohypertension.
Suspect office or “white-coat” hypertension when the BP readings you obtain in the office or clinic are considerably higher than those recorded in the patient’s home. You can confirm white-coat hypertension with 24-hour ambulatory BP monitoring or by having patients monitor pressures at home over several weeks. Pseudohypertension may be observed in elderly patients with severe generalized atherosclerosis. This condition may lead to a very stiffened, calcified brachial artery, which yields falsely elevated BP readings. Clinical clues to this condition are:

•Marked hypertension in the relative absence of target organ damage, or
•Symptoms that suggest overtreatment in the absence of excessive reductions in auscultated BP.

Confirmation of pseudohypertension requires intra-arterial assessment of BP.

2. Consider patient noncompliance.
This is a pervasive problem and a major contributor to poor control of hypertension. Almost 50% of patients discontinue a medication within 6 months of its initial prescription because of:

•A perceived lack of efficacy.
•Adverse reactions.
•Poor communication between patient and physician.
•Inconvenient dosing.
•Medication costs.

Nonadherence may take the form of prolonged dosing intervals, skipped doses, or brief drug “holidays,” as opposed to total discontinuation of the medication.

3. Make sure the regimen is adequate. In the compliant patient, inadequate dosing may contribute significantly to resistant hypertension. Other factors include physician reluctance to prescribe combination therapy, to set a treatment goal with each patient, and to treat to that goal. An inadequate treatment regimen is the leading cause of resistance among patients referred to a hypertension clinic. This is most commonly attributable to a lack of a prescription for-or to inadequate dosages of- a diuretic.24. Is another drug interfering with antihypertensive therapy? Be sure to ask the patient about other drugs he or she may be taking. A variety of prescription and/or nonprescription agents may interact with the antihypertensive regimen. Most commonly missed are the over-the-counter agents, such as NSAIDs, nasal sprays, oral decongestants, and appetite-suppressants. All of these agents can induce hypertension or interfere with the action of selected antihypertensive drugs. A number of prescription as well as illicit drugs can also contribute to apparent resistance to treatment.

5. Rule out associated conditions.
Never underestimate the importance of selected associated conditions. Excessive alcohol intake is the most common cause of reversible hypertension in our society, and both young and elderly patients must be questioned directly. Obstructive sleep apnea has been associated with resistant hypertension among patients who present with clinical features of obesity, excessive drowsiness, and observed apneic episodes during sleep. Obesity and insulin resistance can contribute to sodium and water retention and resistance to antihypertensive therapy.

6. Could excess salt and volume expansion be to blame? Do not overlook excessive sodium intake and plasma volume expansion. Look for patients whose dietary history suggests inappropriate sodium restriction: an inexpensive 24-hour urine collection for sodium may provide valuable information. Some antihypertensive agents can actually induce sodium retention and volume expansion if they are not taken with a diuretic. Make sure your patient is receiving and taking an appropriate dose of an oral diuretic.

Your evaluation up to this point can be accomplished entirely in the office. If you have followed these steps, you will have ruled out approximately 85% of patients suspected of having resistant hypertension.

7. Look again for a secondary cause. If the above measures fail to reveal the cause of refractory hypertension, it may be time to reassess your patient for a secondary and potentially reversible cause of hypertension that may have been missed. Clinical clues to selected secondary forms of hypertension are well established but require additional specific diagnostic testing. At this point, you may feel more comfortable referring your patient to a hypertension specialist to complete the evaluation.

8. Modify the regimen. If you have ruled out a secondary cause of hypertension, consider revisions in drug therapy. Review the first 6 steps of the evaluation to ensure that each has been carefully and thoroughly addressed. Your patient should be on a regimen of no fewer than 3 antihypertensive agents from different classes-including a diuretic-in maximum recommended doses. Add additional agents from other classes or consider substituting 1 or more drugs already in the regimen. Options include selected agents that are not considered initial therapy, such as central agonists (eg, clonidine or guanfacine), a peripheral adrenergic inhibitor (guanethidine), or a potent direct vasodilator (minoxidil). Additional incremental doses of a long-acting diuretic, such as metolazone, or multiple daily doses of a loop diuretic may be beneficial in treating resistant hypertension accompanied by renal insufficiency. In patients with normal renal function, the addition of a loop diuretic to a long-acting thiazide diuretic may be helpful.

9. Refer for further evaluation.
For the 3% to 5% of patients with resistant hypertension who reach this point in the evaluation, consider a noninvasive hemodynamic and neurohumoral evaluation. The goal is to help identify a mechanism for resistance, such as volume expansion; increased cardiac output or peripheral resistance; or increased levels of circulating catecholamines, angiotensin II, or aldosterone.

10. Selectively amend the regimen.
The finding of a potential mechanism for sustained hypertension will often allow a targeted change in medications, such as:

•An increase in diuretic use for the patient with expanded plasma volume, or
•The addition of a β-blocker for the patient with elevated cardiac output.

Specific inhibitors of the renin angiotensin–aldosterone system are also available. The ultimate goal is control of BP to currently recommended treatment goals in an effort to minimize the risk of cardiovascular morbidity and mortality. Thorough attention to the steps outlined above should facilitate identification of the cause of the resistant hypertension in the vast majority of patients.




The sixth report of the Joint National Committee on the prevention, detection, evaluation and treatment ofhigh blood pressure.

Arch Intern Med.



Vidt DG. Refractory hypertension. In: Antman EM, ed.

Cardiovascular Therapeutics: A Companion toBraunwald’s Heart Disease.

2nd ed. Philadelphia: WB Saunders Company; 2002:810-816.