Understanding refractory hypertension

C. VENKATA S. RAM, MD, Texas Blood Pressure Institute, Director, Medical Education and Clinical Research, Dallas Nephrology Associates; and Clinical Professor of Internal Medicine, University of Texas Southwestern Medical Center, Dallas. Dr Ram, who has written more than 240 articles and a book on the treatment of hypertension, is Deputy Editor of the Journal of Human Hypertension and the American Journal of Cardiovascular Drugs.

Refractory hypertension is a possibility when BP remains uncontrolled even for patients on a triple-drug regimen. A careful investigation into possible causes guides the choice of therapy.

Refractory or resistant hypertension is somewhat less common than other forms of hypertension, especially with the advent of modern therapeutic agents. In fact, a majority of patients with primary hypertension respond favorably to one or more antihypertensive drugs. Definitions vary, but hypertension is usually considered refractory if BP cannot be reduced below target levels in patients who are compliant with an optimal triple-drug regimen that includes a diuretic. In patients with isolated systolic hypertension (ISH), refractoriness has been traditionally defined as a failure of multiple antihypertensive drugs to reduce systolic BP to below 160 mm Hg. Recent observations strongly indicate that the target level for systolic BP should be no higher than 140 mm Hg, however (see Table 1).

 

TABLE 1 JNC 7 hypertension classifications
BP classification	Systolic BP (mm Hg)	And/ or	Diastolic BP (mm Hg)
Normal	<120	And	<80
Prehypertension	120-139	Or	80-89
Stage I hypertension	140-159	Or	90-99
Stage II hypertension	>160	Or	>100
Adapted with permission from Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.

WHY DOES THE BP REMAIN ELEVATED?

When BP goals are not attained with standard antihypertensive drug therapy, the first steps are to determine whether the patient does have refractory hypertension and to consider some possible etiologies (see Table 2). What environmental factors might be to blame for resistant hypertension? Is the patient adhering to the prescribed regimen? Is pseudoresistance present? Are drug interactions or adverse reactions at fault? Does the patient have a secondary form of hypertension such as renovascular hypertension? Could pressor mechanisms be responsible for elevating the arterial BP despite antihypertensive drug therapy?

 

TABLE 2 Causes of refractory hypertension

Pseudoresistance    White-coat hypertension    Pseudohypertension in older patients    Use of small cuff in obese patients Nonadherence to prescribed therapy Volume overload Drug-related causes    Dosages too low    Wrong type of diuretic    Inappropriate combinations    Drug actions and interactions       Sympathomimetics       Nasal decongestants       Appetite suppressants       Cocaine       Caffeine (?)       Oral contraceptives       Adrenal steroids       Licorice (may be found in chewing tobacco)       Cyclosporine       Tacrolimus       Epoetin alfa       Antidepressants       NSAIDs Concomitant conditions    Obesity    Sleep apnea    Ethanol intake >1 oz (30 mL) per day    Anxiety, hyperventilation Secondary causes of hypertension (eg, renovascular hypertension, adrenal causes, and renal disease, etc.)

Pseudoresistance and pseudohypertension

In some patients, clinic or office BP measurements may be higher than those obtained outside the office setting, an example of so-called white-coat hypertension or pseudoresistance. Although white-coat hypertension is often considered in the context of mild hypertension (stage I), some cases of refractory hypertension may be manifestations of white-coat hypertension. Patients who may have refractory white-coat hypertension do not demonstrate indices of target-organ damage despite very high BP readings recorded in the office or clinic. The disparity between a patient's apparent hypertension and the lack of target-organ damage can be resolved by measuring BP at home or by obtaining ambulatory BP recordings in selected patients with an automatic device.^1-3

The condition termed pseudohypertension is sometimes seen in elderly patients. BP measurements produce falsely elevated readings when a hardened, sclerotic artery cannot be compressed (Osler's phenomenon).⁴ Persistently high readings in the absence of target-organ damage or dysfunction—as in the case of pseudoresistance—raise the possibility of pseudohypertension. The prevalence of pseudohypertension is unknown. While some experts have advocated the use of intra-arterial BP determination as a means of accurately making this diagnosis, I do not recommend this procedure to document pseudohypertension because of its impracticality.

Pseudohypertension is more commonly attributable to a measurement artifact—elicited by taking a BP with a manometer cuff that is too small to be wrapped correctly around the patient's arm.⁵ To ensure an accurate determination, BP should be measured with an appropriate-sized cuff while the patient is seated and the arm supported at heart level. The bladder within the cuff should encircle at least 80% of the arm diameter. Be cautious, however, before dismissing an elevated BP reading as the product of a measurement artifact, because patients with high BP caused by truly refractory hypertension experience a high rate of cardiovascular and other complications.

 

Drugs mentioned in this article

Cholestyramine (LoCHOLEST, Prevalite, Questran) Cyclosporine (Gengraf, Neoral, Sandimmune) Epoetin alfa injection (Epogen, Procrit) Furosemide (Lasix) Guanethidine Hydralazine (Apresoline) Hydrochlorothiazide Indomethacin (Indocin) Minoxidil (Loniten) Phenylpropanolamine Propranolol (Inderal) Rifampin (Rifadin) Tacrolimus (Prograf)

Nonadherence to a medication regimen

Failure to follow a prescribed regimen is perhaps the most common cause of suspected refractory hypertension. Patients may have good reasons for not adhering to the treatment plan, such as side effects, costs, and complexity of the drug regimen. Prescribing generic medications or combination antihypertensive medications may alleviate some of these difficulties. Social, economic, and personal factors may also play a role in nonadherence.

Volume overload

Volume overload may not only increase BP but may also offset the BP-lowering effects of antihypertensive drugs.⁶ Excessive salt intake increases the plasma volume and causes resistance to antihypertensive drugs and can actually raise BP in some patients. Elderly and African American patients are particularly sensitive to fluid overload, as are patients with renal insufficiency and congestive heart failure (CHF). Some antihypertensive drugs such as direct vasodilators, antiadrenergic agents, and most of the nondiuretic antihypertensive drugs cause plasma and extracellular fluid expansion, thus interfering with BP control. Of the nondiuretic antihypertensive drugs, ACE inhibitors, angiotensin receptor blockers, and calcium antagonists are least likely to cause fluid retention. Antihypertensive responsiveness can be regained by restricting sodium intake, adding a diuretic or increasing its dosage, and, in many instances, by switching from a thiazide-type to a loop diuretic.

Drug-related hypertension

Hypertension may seem to be refractory if antihypertensive drugs are used in suboptimal dosages or when an inappropriate diuretic is prescribed—such as the use of a thiazide-type diuretic rather than a loop diuretic in a patient with renal insufficiency or CHF or someone who is taking a potent vasodilator such as minoxidil or hydralazine. Adverse drug-drug interactions can raise the BP in normotensive as well as in hypertensive patients. Such adverse interactions can occur as a result of alterations in drug pharmacokinetics or in pharmacodynamics of drugs administered concomitantly for different indications (see Table 3). Hypertension associated with renal insufficiency is often difficult to treat; hypertensive patients with reduced renal function generally require concomitant therapy with a loop-diuretic such as furosemide, since the thiazide-type diuretics do not work well in such patients.

 

TABLE 3 Drug interactions implicated in resistant hypertension
Antihypertensive agents	Interacting drugs
Hydrochlorothiazide Propranolol Guanethidine ACE inhibitors, diuretics Centrally acting drugs All drugs	Cholestyramine Rifampin Tricyclic antidepressants Indomethacin Tricyclic antidepressants Cocaine Phenylpropanolamine

Of all the drugs listed in Table 3, the NSAIDs are particularly important because of the frequency with which they are used in clinical practice; these drugs attenuate the vasodilatory actions of intrarenal prostaglandins, thus inhibiting natriuresis, which leads to volume expansion and BP elevation.⁷ Therefore, if possible, NSAIDs should be avoided in patients with refractory or severe hypertension. The estrogen component of oral contraceptives may increase BP, but hormonal replacement therapy has no significant adverse effect on BP.

Concomitant medical conditions

It has been reported that cigarette smoking can interfere with BP regulatory mechanisms.⁸ Obesity is often a factor in the genesis of refractory hypertension. Obstructive sleep apnea is being increasingly recognized as a possible factor in the development of resistant hypertension.⁹ Excessive alcohol consumption (more than 1 oz [30 mL]) clearly raises the systemic BP, sometimes to dangerously high levels.¹⁰ Members of our group have witnessed panic attacks and hyperventilation as a possible causative factor in a few patients with refractory hypertension. Chronic pain may also aggravate hypertension.

Secondary causes

In a small percentage of patients with refractory hypertension, the underlying cause may be a secondary form of hypertension, such as renovascular hypertension (see Table 4). Patients with a secondary form of hypertension may present with drug-resistant hypertension. A sudden loss of efficacy of a previously effective antihypertensive regimen should raise the index of suspicion for renovascular disease or other secondary forms of hypertension.¹¹

 

TABLE 4 Secondary forms of HTN resistant to conventional therapy

Renovascular hypertension Primary aldosteronism Pheochromocytoma Hypothyroidism Hyperthyroidism Hyperparathyroidism Aortic coarctation Key: HTN, hypertension.

EVALUATION

Rational management of refractory hypertension requires a systematic approach based on the cause of an elevated BP in a particular patient. Uncontrolled hypertension can cause significant morbidity and mortality, so unreasonable changes in the treatment plan should be avoided. An overall management approach should be based on a careful evaluation and rational medical therapy.

When either pseudoresistance, white-coat hypertension, pseudohypertension, or the presence of a measurement artifact are possible causes of refractory hypertension, it may be appropriate to obtain home BP readings and/or 24-hour ambulatory BP recordings to document whether or not the patient experiences hypertension outside the office/clinic setting, and if so, to what degree.¹² BP should always be measured with a large cuff when the patient is obese.

Once the validity of the BP measurement is confirmed, it is critical to ascertain the that the patient is adhering to a prescribed regimen. Nonadherence to a treatment plan is often an issue and this possibility must be considered before an extensive and unnecessary patient evaluation is undertaken.^13,14 If nonadherence is a problem, the first thing to do is to identify and correct contributory factors.^15-18 As a first step, treatment should be simplified to the extent possible. This approach may encourage patient participation, and if the patient-physician rapport is good, determining blood drug levels to assess adherence should be unnecessary.

Correction of volume overload is a key strategy in managing resistant hypertension. Excessive salt intake must be curtailed. Appropriate diuretic therapy should be implemented, and the choice of a drug and its dosage should take into account the possibility of volume overload. Patients with concomitant CHF or renal insufficiency require optimal volume control to achieve adequate BP control. Antihypertensive drug dosages should be titrated systematically to determine whether the patient is responding to treatment. Drug interactions should be considered, and patients should be asked about their use of any drug that could increase BP, including corticosteroids, oral contraceptives, sympathomimetics, nasal decongestants, cocaine, and appetite suppressants. Patients should be counseled about alcohol consumption, weight control, salt intake, and regular physical activity. Conditions such as obstructive sleep apnea or chronic pain should be treated.

Secondary causes of hypertension such as those listed in Table 4 should be considered in the ultimate evaluation of patients with resistant hypertension. Based on the clinical characteristics, renovascular hypertension should be pursued in patients with truly refractory hypertension. Other secondary causes of hypertension such as primary hyperaldosteronism, pheochromocytoma, Cushing's syndrome, coarctation of aorta, and renal disease should be considered based on the clinical course and laboratory findings. If an underlying cause is found, it should be corrected to permit better BP control. Patients who have refractory hypertension experience and suffer from a high degree of target-organ damage.¹⁹

DRUG TREATMENT

Even if a correctable cause is not found, patients with refractory hypertension require aggressive drug therapy. The first step is to optimize therapy either by increasing dosages in the existing regimen or changing drug combinations and then observing the outcome for few weeks. Effective diuretic therapy should be implemented. If the patient has failed to respond to conventional therapies, consideration should be given to the use of hydralazine or minoxidil. Because direct vasodilators cause significant reflex activation of sympathetic nervous system and fluid retention, they should be coadministered with a beta-blocker and a diuretic (usually a loop diuretic). I generally give a trial of hydralazine therapy before prescribing minoxidil. Occasionally, further reductions in BP can be secured by adding a fourth agent such as oral or transdermal clonidine. In patients with marked renal impairment, dialysis may be required for adequate BP control.

 

Clinical Pearl "One must be cautious before dismissing an elevated reading as a measurement artifact, because patients with truly refractory hypertension experience a high rate of cardiovascular and other complications." — C. Venkata S. Ram, MD

PRODUCED BY MARY DESMOND PINKOWISH

Dr Ram consults and is on the speakers' bureau for a number of pharmaceutical companies, including Biovail Pharmaceuticals, Bristol-Myers Squibb, Novartis, and Pfizer, Inc.

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15. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.

16. Graves J. Management of difficult-to-control hypertension. Mayo Clin Proc. 2000;75:278-284.

17. Setaro J, Black H. Refractory hypertension. N Engl J Med. 1992;327: 534-547.

18. Eraker SA, Kirscht JP, Becker MH. Understanding and improving patient compliance. Ann Intern Med. 1984;100:258-268.

19. Cuspidi C, Macca G, Sampieri L, et al. High prevalence of cardiac and extracardiac target organ damage in refractory hypertension. J Hypertens. 2001:19:2063-2070.

 

Understanding refractory hypertension. Patient Care May 2004;38:12-16.