Getting to the Heart of "Refractory" Hypertension

August 1, 2006

How can I control elevated blood pressure (BP) in an older patient who is already taking 4 antihypertensive agents?

Q: How can I control elevated blood pressure (BP) in an older patient who is already taking 4 antihypertensive agents?

A: In most persons with systolic and diastolic hypertension, control can be achieved with 3 or 4 antihypertensive agents, particularly if 1 of those agents is an oral diuretic. Secondary causes of hypertension are found in fewer than 10% of patients who have hypertension that is refractory to an adequate regimen of antihypertensive agents. Thus, the first step in the management of refractory hypertension should not be the ordering of additional diagnostic studies in search of a secondary cause. More appropriate is a systematic approach to rule out a number of conditions-such as nonadherence-that are much more frequent causes of apparently refractory hypertension.1

Nonadherence. Direct but nonconfrontational questioning remains the best means of identifying nonadherence, and this can be accomplished during an office visit. Nonadherence may result from such factors as medication costs, inadequate patient education, complexity of the regimen, and inconvenient dosing. Early dementia and/or cognitive deficits may play a role, particularly among older patients. Adherence problems can extend to such lifestyle measures as caloric restriction and weight control, reduced salt or alcohol intake, and exercise programs. Make your patients aware of the overall treatment goals (such as lifestyle changes) as well as their BP readings. Be sure they understand that combination therapy will probably be required to achieve target BP levels.

Suboptimal treatment regimen. Ascertain whether the treatment regimen is adequate and appropriate. Studies have shown that the most frequent cause of refractory hypertension is a suboptimal treatment regimen. Failure to include a diuretic and reluctance to titrate other drugs in the regimen are the principal reasons that some medications-although approved for once-daily administration-may not provide 24-hour coverage when prescribed at lower dosages.

Adverse effects can lead to nonadherence. Be sure to make your patients aware of potential adverse effects that may be related to any newly prescribed drug and encourage them to call your office if they wish to discontinue a prescribed drug for any reason.

Medication review. Carefully review all of your patients' current medications, because some may have been prescribed by other practitioners. Many agents prescribed for other indications have been associated with hypertension. Among the more common are corticosteroids, oral contraceptives, NSAIDs, and a host of over-the-counter decongestants and appetite suppressants that contain vasoactive compounds such as phenylpropanolamine, ephedrine, and pseudoephedrine.

Patients rarely share information about use of recreational drugs or excessive amounts of alcohol. Question them about their use of such substances and explain the role they may play in refractory hypertension.

White-coat hypertension. Ascertain whether your patient has sustained elevations in BP by determining whether BP measurements outside the office have been obtained and whether they coincide with your office readings. A patient whose out-of-office readings are consistently lower than office readings may have white-coat hypertension. You may wish to consider having the patient purchase or be provided with an automated oscillometric device to provide a series of out-of-office BP readings over a period of 1 to 2 weeks. Out-of-office readings may demonstrate good control in a patient whose office readings suggest poorly controlled hypertension.

Other conditions. A variety of conditions may contribute to persistently elevated BP despite an apparently appropriate treatment regimen. Obstructive sleep apnea is now considered the most likely cause of refractory hypertension.2 As many as 50% of patients with hypertension may have some degree of significant sleep disorder; moreover, many patients may not present with the symptoms typically associated with sleep apnea (marked obesity, snoring, and observed apneic episodes at night).

Excessive alcohol intake may lead to persistently elevated BP. Age is not a limiting factor; the problem has been observed in younger as well as older adults. Persons who smoke more than 2 packs of cigarettes per day often show persistently elevated BP and increased BP variability.

Hyperinsulinemia is now being observed in epidemic proportions in association with obesity, hypertension, and the metabolic syndrome. It contributes to sodium retention, increased vascular resistance, and secondary activation of the renin-angiotensin-aldosterone system that results inelevated BP.3

Finally, the absence of edema in a patient with refractory hypertension should not deter you from seeking evidence of excessive sodium intake and intravascular volume expansion. Strict adherence to a sodium-restricted diet and/or possible adjustment of the diuretic dosage may result in significant reductions in BP without other changes in the treatment regimen.

Pseudohypertension. A few elderly patients with isolated systolic hypertension and severe atherosclerosis may have pseudohypertension, a condition characterized by cuff pressure that is inappropriately high compared with intra-arterial pressure because of extensive atheromatous changes in the brachial arteries.4 Clinical clues may include a relative absence of target organ damage despite the severe hypertension, radiologic evidence of pipestem calcification in the brachial arteries, and brachial artery pressure that may be higher than lower extremity pressures. Renal artery stenosis in association with extensive atherosclerotic disease is also found more commonly in these patients. Regardless of age, patients with isolated systolic hypertension are at increased cardiovascular risk if their hypertension is not aggressively treated and controlled.

The next step. Once you have addressed the common causes of "refractory" hypertension-or determined that they are absent-a more focused history and clinical examination may be warranted to uncover clues to a secondary cause that may have developed since the initial diagnosis or that may not have been evident at that time.5 Clinical clues may help determine which additional diagnostic studies are required to identify a secondary cause.


REFERENCES:1. Vidt DG. Pathogenesis and treatment of resistant hypertension. Minerva Med. 2003;94:201-214.
2. Goodfriend TL, Calhoun DA. Resistant hypertension, obesity, sleep apnea, and aldosterone theory and therapy. Hypertension. 2004;43:518-524.
3. Hall JE. The kidney, hypertension and obesity. Hypertension. 2003;41:625-633.
4. Zuschke CA, Pettyjohn FS. Pseudohypertension. South Med J. 1995;88:1185-1190.
5. Schreiber MJ Jr, Vidt DG. Hallmarks of essential and secondary hypertension. In: Stoller JK, Michota FA, Mandell BF, eds. The Cleveland Clinic: Intensive Review of Internal Medicine. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:599-613.