Untreated and uncontrolled hypertension is a major health problem in the United States. Findings from the Third National Health and Nutrition Examination Survey (NHANES III, phase 2)¹ conducted from 1991 to 1994, suggest that only 53 percent of patients with hypertension are being treated with prescription medication, and only 27 percent have their hypertension under control (defined as blood pressure less than 140/90 mm Hg). This was true despite a high level of patient awareness (69 percent) of their condition. Because 24 percent of all adults in the United States, or an estimated 43 million Americans, have hypertension, the findings of NHANES III suggest that over 30 million Americans are at increased risk of cardiovascular disease as a result of uncontrolled hypertension. The risk is even greater in the non-His-panic black population, where the prevalence of hypertension is estimated to be 32 percent.

Although relatively rare, identification of secondary hypertension is important because it is frequently resistant to usual antihypertensive medications and may be controlled by interventions directed at the underlying cause. The evaluation and treatment of patients with secondary hypertension is beyond the scope of this article. However, the most common forms of secondary hypertension in patients have been recently reviewed.^2–5

Antihypertensive treatment as generally administered in the United States does not lower blood pressure into the optimal range (less than 120/80 mm Hg), where cardiovascular risk is lowest. Whether more aggressive antihypertensive treatment would improve blood pressure control and reduce the morbidity and mortality associated with cardiovascular disease is an important question that remains unanswered. The first aim of therapy for most patients should be to achieve blood pressure levels of less than 140/90 mm Hg.

The reasons for failure to control blood pressure in the majority of people with hypertension are complex (Table 1).⁶ “True” resistant hypertension, defined as hypertension that remains uncontrolled (140/90 mm Hg or higher) despite an optimal two-drug regimen that has had adequate time to work (at least one month since last drug or dosage adjustment) occurs in 10 percent or fewer patients with essential hypertension, and secondary hypertension is even less common.⁷ The major causes of uncontrolled hypertension are inadequate therapy, patient noncompliance and inappropriate therapy.

Inadequate Therapy

Drug- and Dosage-related Causes

A frequent cause of failure to control blood pressure is the use of inappropriately low dosages of antihypertensive drugs. This error can be avoided if physicians become thoroughly familiar with one or two drugs in each class of antihypertensive medications and follow the manufacturer's recommendations for their use. Doses should be titrated upward until blood pressure is controlled or the maximum recommended dosage is reached, unless the patient experiences dose-related adverse effects. It is then appropriate to add a drug from another class that has additive or synergistic effects with the first drug. Unless the patient has symptoms related to accelerated hypertension, the interval between dose adjustments should be four weeks or more. This amount of time is needed for any dosage of antihypertensive medication to reach its full therapeutic benefit.

The use of inappropriately low dosages of individual antihypertensive drugs inevitably leads to multiple-drug regimens, which reduces compliance. Furthermore, even when optimal drug dosages are administered, polypharmacy is difficult to avoid because blood pressure can be controlled by using one drug in only about 50 percent of patients. Fixed-dose combination therapy is designed to improve patient compliance by decreasing the number of pills that must be taken and reducing the dose-dependent adverse effects of individual components (Table 2).⁸ In order to be combined in a single-dose form, federal law requires that each component in the combination must contribute to lowering blood pressure and that the dosage of each component must be such that the combination is safe and effective in a major proportion of the target population (i.e., patients whose hypertension is not easily controlled with a single drug). Most fixed-dose combinations currently available contain one or two diuretics (one for natriuresis, the other for potassium sparing), since diuretics enhance the antihypertensive efficacy of all the other classes of agents (Table 3).⁸

Furthermore, a recent study⁹ has demonstrated that combination therapies containing a diuretic are more effective than those not containing a diuretic. The new combinations of angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers offer promise, as the ACE inhibitors reduce the peripheral edema that frequently develops with dihydropyridine calcium channel blocker therapy.

Short-acting antihypertensive agents, including not only calcium channel blockers such as capsular nifedipine (Adalat, Procardia) but also oral clonidine (Catapres), hydralazine (Apresoline) and captopril (Capoten), should generally be avoided because of the need for frequent dosing, leading to noncompliance. In addition, these agents (with the exception of captopril) tend to activate the sympathetic nervous system, resulting in unstable blood pressure control and periods of “rebound hypertension” at the end of the dosing interval.

Patient Factors

Obesity. Obese patients (defined as patients with a body mass index greater than 27.8 in men and 27.3 in women) do not respond as well as leaner patients to antihypertensive medication.^7,10

Thus, weight reduction is a particularly important adjunct to drug therapy in the obese patient with resistant hypertension. Progressively higher doses of antihypertensive drugs are required to control blood pressure as the body mass index increases.¹⁰ However, even lean patients with hypertension, glucose intolerance and hyperinsulinemia may require higher drug dosages, suggesting that obesity, a sedentary lifestyle, glucose intolerance and insulinemia, all of which are related to insulin resistance, may cause refractory hypertension.^7,10

Alcohol Abuse. Excess alcohol intake raises blood pressure in both treated and untreated patients with hypertension, and blood pressure either returns to normal or becomes easier to control when alcohol intake ceases.^7,11 Alcohol abuse is also a frequent cause of non-compliance with medications.

Sleep Apnea. Sleep apnea affects 2 to 4 percent of middle-aged adults, most of whom are unaware they have this disorder.¹² Associations between sleep apnea and both diurnal hypertension and morbidity and mortality due to cardiovascular and cerebrovascular causes have been reported.^12,13 The association between sleep apnea and diurnal hypertension is independent of obesity, age and sex, and appears to be related to stimulation of the sympathetic nervous system by repetitive upper-airway closure.¹⁴ A sleep study is indicated in patients with resistant hypertension and other signs and symptoms of sleep apnea, including obesity, large neck size (size 17 or greater in men and size 16 or greater in women), excessive loud snoring, interrupted sleep, daytime somnolence, polycythemia and carbon dioxide retention.^7,12

Volume Overload

Volume overload, whether related to excess sodium intake or inadequate/inappropriate diuretic treatment, is the most common cause of resistant hypertension in patients who adhere to therapy.⁷ All patients with hypertension should be counseled to avoid foods high in sodium and to increase their consumption of fruits, vegetables and low-fat dairy products. These foods contain micronutrients that reduce the pressor effects of concomitant sodium intake. In patients with hypertension and normal renal function, thiazide diuretics are more effective than loop diuretics in lowering blood pressure.^7,15

One of the main reasons for resistant hypertension may be a failure to include diuretics in the treatment regimen. In the rush to use newer agents, the use of diuretics has decreased dramatically in the past 10 years despite increasing evidence of their long-term safety and benefical effect. Loop diuretics are necessary to control blood pressure and volume in patients with renal dysfunction (glomerular filtration rate less than 30 mL per minute; serum creatinine approximately 3 to 4 mg per dL [260 to 350 mmol per L]).^7,16 This is a particular problem in patients with progressive hypertension-induced renal damage, as well as in patients with fluid retention either secondary to a reduction in blood pressure or to the effects of other classes of antihypertensive drugs (particularly direct vasodilators and centrally acting adrenergic agents). A switch to a loop diuretic may be indicated in these patients.

Nonadherence to Therapy (‘Noncompliance’)

Failure to follow a prescribed drug regimen has been implicated in approximately 50 percent of patients with resistant hypertension.^7,17–19 Nonadherence to therapy can be attributed to a variety of factors, including cost of medication and related care, inadequate patient education, complex drug regimen, the patient's level of literacy and education, and the adverse side effects of the medication. Nonadherence to therapy should be a primary consideration in the evaluation of all patients with difficult-to-manage hypertension. Clues to nonadherence include frequently missed appointments, failure to manifest the expected biologic effects of prescribed drugs (e.g., slowing of heart rate with use of beta-adrenergic blockers) and alcohol or other substance abuse.⁷

Adherence to antihypertensive treatment can be enhanced by using the strategies outlined in Table 4.¹⁹ The cornerstone of these strategies is the establishment of a good relationship with the patient, and free and open communication about hypertension, its complications and the goals and pitfalls of treatment. In a world where physicians' time is severely limited, educational messages can be delivered by office personnel, written material or video presentations.

A positive and supportive approach to treatment combined with the message that an effective, affordable and convenient drug regimen relatively free of side effects can be found for almost every patient yields the best results. The large number of antihypertensive medications now available, including sustained-release preparations and fixed-dose combinations, have made once-a-day dosing and smooth 24-hour control of blood pressure a reality, improving the tolerability of multidrug antihypertensive regimens. Above all, the physician must be convinced that treating to reach a goal blood pressure level of less than 140/90 mm Hg is worthwhile.

Inappropriate Therapy

‘White Coat’ Hypertension

“White coat” or office hypertension occurs when blood pressure values measured by a health care professional in the office or clinic are significantly elevated compared with blood pressure values measured outside the health care setting (i.e., by ambulatory monitoring or patient self-measurement).²⁰ White coat hypertension has been reported in 21 to 39 percent of patients with untreated hypertension.^21,22 Prospective studies have not defined the natural history or the mortality and morbidity risks associated with untreated white coat hypertension, but cross-sectional studies^23,24 suggest that, when compared with normotensive patients, patients with white coat hypertension have higher left ventricular mass indices, higher low-density lipoprotein cholesterol and insulin levels, reduced diastolic compliance in the left ventricle, and abnormal elasticity, compliance and stiffness in the large arteries. Thus, white coat hypertension appears not to be a benign condition but perhaps a mild form of essential hypertension associated with increased cardiovascular risk.

White coat hypertension should be suspected in patients who remain resistant to therapy in the absence of target organ damage (retinopathy, renal insufficiency, left ventricular hypertrophy), who manifest symptoms of overmedication (orthostatic symptoms, persistent fatigue) and/or who report home blood pressure values significantly lower than values measured in the office. Because white coat hypertension is so common, all patients with hypertension should be encouraged to obtain home blood pressure values.

Ambulatory monitoring and blood pressure self-measurement are also helpful in patients with apparent drug resistance, episodic hypertension or autonomic dysfunction, and in patients with hypotensive symptoms who take antihypertensive medications. Extensive evidence indicates that ambulatory blood pressure values or blood pressure self-measurement correlates more closely than office blood pressure values with target organ damage.²⁵ Although treatment guidelines have not been defined for white coat hypertension, careful follow-up and antihypertensive treatment are indicated, particularly in patients developing signs of target organ damage.²⁴

Once white coat hypertension is diagnosed, accurate home blood pressure values are the best guide for therapy. To maximize accuracy, the patient should be encouraged to obtain a quality arm or wrist (not finger) cuff device. The patient should initially bring the device to the office to ensure that he or she knows how to use it properly and to have its accuracy validated against a calibrated mercury sphygmomanometer.

Pseudohypertension

Pseudohypertension is a falsely elevated blood pressure obtained by indirect cuff measurement secondary to loss of arterial compliance, necessitating increased cuff pressure in order to compress the underlying artery.²⁶ Loss of arterial compliance is usually secondary to atherosclerosis, occurring most commonly in the elderly. The Systolic Hypertension in the Elderly Program (SHEP)²⁷ study group determined that 7 percent of the elderly screened had pseudohypertension. Diagnosing hypertension when the patient actually has pseudohypertension can lead to overmedication of the patient. Pseudohypertension should be suspected in elderly patients whose blood pressures remain elevated despite therapy, who have little or no evidence of target organ damage or who manifest symptoms of overmedication.

Diagnosis of pseudohypertension is problematic. The Osler maneuver, in which the radial or brachial artery remains palpable when the blood pressure cuff is inflated above the auscultated systolic pressure, has been advocated as a screening test for pseudohypertension,²⁸ but its diagnostic value has been questioned.²⁹ A definitive diagnosis of pseudo-hypertension requires direct measurement of intra-arterial blood pressure but, since this is a hazardous procedure, blood pressure may be measured by using an automatic infrasonic or plethysmographic device (2300 Finapres blood pressure monitor. Ohmeda, Ohmeda Drive, P.O. Box 7550, Madison, WI 53707; telephone: 800-345-2700-7550), with recording from a finger as an alternative.³⁰