Chapter 44. Refractory Hypertension

• Blood pressure above the recommended values (140/90 mm Hg) despite the use of greater than or equal to 3–4 antihypertensive agents, each belonging to a different class.
• Insufficient treatment prescription and lack of adherence to prescribed drugs, dietary restrictions, and lifestyle recommendations are the most frequent causes.
• Associated with obesity, sleep apnea, diabetes, chronic kidney disease, advanced age, high dietary salt intake, and black race.

As the 21st century unfolds, hypertension remains a challenging medical problem. Hypertension continues to be a common reason for office, urgent care center, and emergency room visits. If not properly controlled, hypertension can lead to blindness, renal failure, heart disease, and stroke. In spite of the establishment of extensive health action programs, blood pressure (BP) values remain above the recommended objectives in the majority of patients with hypertension. Data from the National Health and Nutrition Examination Survey 1999–2000 showed that in only 34% of all persons with hypertension in the United States was blood pressure controlled to meet recommended values. Similar data come from different countries.

Common factors associated with the development of resistant hypertension include obesity, sleep apnea, diabetes, chronic kidney disease, advanced age, high dietary salt intake, and black race. Interfering substances such as nonsteroidal anti-inflammatory drugs and excessive alcohol consumption can worsen blood pressure control. However, an insufficient treatment prescription and the lack of adherence to the prescribed drug and lifestyle recommendations (eg, the moderation of alcohol consumption, the restriction of salt intake, the reduction of body weight) seem to be the most frequent causes of uncontrolled BP. Other causes of resistance to treatment include cases of spurious hypertension, such as isolated office (white-coat) hypertension, and failure to use large cuffs on large arms. Nevertheless, a significant number of patients adequately diagnosed and treated still have uncontrolled BP. The real prevalence of refractory hypertension is difficult to determine. Published studies describe a prevalence that oscillates between 3% and 30% in hypertension units. Further, the existence of different diagnostic and therapeutic strategies makes a comparison between different published studies difficult.

This review focuses on those causes of resistance to treatment that can be evaluated in the outpatient setting. These include a search for nonadherence, assessing the adequacy of the treatment regimen, and ruling out drug interactions and associated conditions. In the absence of the above factors, assessment for secondary causes of hypertension is appropriate. This careful stepwise evaluation is not only cost effective, but also capable of identifying the contributing factors in the vast majority of patients with apparently resistant hypertension.

The recent joint directives of the European Society of Hypertension/European Society of Cardiology (ESH-ESC) define the treatment of refractory hypertension as a therapeutic plan that includes attention to lifestyle measures and the prescription of at least three drugs (including a diuretic); however, in adequate doses this has failed to lower systolic and diastolic BP sufficiently. Moreover, the VII Joint National Committee report further notes the exclusion of potential causes of secondary hypertension (including the use of agents that may increase BP), with special attention to the type of diuretic and the dose used in the case of renal insufficiency. Both directives agree on the need to refer the patient to a specialist because of frequently associated target-organ damage.

Recent clinical trials indicate that resistant hypertension is common, affecting 20–30% of the different study populations. Such clinical outcome studies provide good estimates of the true frequency of resistant hypertension because they employ an intensive treatment regimen mandating drug titrations if BP remained elevated, provide medications free of charge, and closely monitor adherence to the treatment regime with pill counts.

In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) more than 33,000 subjects aged 55 years or older with a history of hypertension and one other cardiovascular risk factor were randomized to receive chlorthalidone, amlodipine, or lisinopril. The dose of the randomized medication was titrated first; non-study-related antihypertensive medications were then added as long as BP remained above 140/90 mm Hg. After a 5-year follow-up, 34% of subjects had not achieved goal BP, and overall, 27% of subjects were receiving three or more medications.

In the Controlled ONset Verapamil INvestigation of Cardiovascular End Points trial (CONVINCE), more than 16,600 subjects were randomized to controlled-onset, extended-release verapamil or conventional antihypertensive therapy (atenolol or hydrochlorothiazide), with other medications added as necessary to reduce BP below 140/90 mm Hg. After a mean follow-up of 3 years, 33% of subjects had not achieved goal BP and 17–18% of subjects were receiving three or more antihypertensive medications. In studies of even more patients with complicated hypertension, control rates were even poorer.

In the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study, which enrolled hypertensive patients with left ventricular hypertrophy, only 46–49% of subjects had a BP of <140/90 mm Hg after almost 5 years of intensive antihypertensive treatment.

Symptoms and Signs

Table 44–1 lists factors that have been suggested to be causes for resistance; they are often displayed as associated factors in the same patient.

White-Coat Phenomena

Some studies suggest that white-coat or isolated clinic hypertension is as least as common in patients with resistant hypertension as the general population, with a prevalence ranging from 28% to 52%. The white-coat effect is defined as an increase in BP that occurs at the time of a clinical visit and dissipates soon after. It has been known for more than 50 years that BP recorded by a physician can be as much as 30 mm Hg higher than BP taken by the patient at home, using the same technique and in the same posture. Physicians also record higher pressures than nurses or technicians. The white-coat effect is usually defined as the difference between the clinic and daytime ambulatory pressure. The underlying mechanisms are not well understood, but may include anxiety, a hyperactive alerting response, or a conditioned response. The white-coat effect is seen to a greater or lesser degree in most if not all hypertensive patients, but is much smaller or negative in normotensive subjects or those with masked hypertension. A closely linked but discrete entity is white-coat hypertension, which refers to a subset of patients who are hypertensive according to their clinic BP but normotensive at other times.

Secondary Causes of Arterial Hypertension

The most common secondary causes of resistant hypertension are hyperaldosteronism, renal parenchymal disease, renal artery stenosis, and sleep apnea (Table 44–2). However, recent prospective studies indicate that hyperaldosteronism is the most common cause of secondary hypertension.

Table 44–2 lists the symptoms and signs frequently associated with secondary hypertension; these can guide us toward undertaking the necessary diagnostic tests in each case.

Hyperaldosteronism

Hyperaldosteronism is being increasingly recognized as a common underlying cause of hypertension. In an extensive evaluation that included more than 600 subjects with hypertension, Mosso et al reported that the prevalence of aldosteronism increases according to the severity of the hypertension. Applying the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure sixth report staging criteria to untreated subjects, primary aldosteronism was diagnosed in 2% of subjects with stage 1 hypertension (140–159 mm Hg/90–99 mm Hg), 8% of subjects with stage 2 hypertension (160–179 mm Hg/100–109 mm Hg), and 13% of subjects with stage 3 hypertension (>180/110 mm Hg). This is just one of many reports that indicate a prevalence of hyperaldosteronism of 15–30% among general and selected hypertensive populations.

Primary aldosteronism (PA) is particularly common in subjects with resistant hypertension. In a prospective evaluation of African-American and white subjects with resistant hypertension, defined as uncontrolled hypertension despite use of three or more antihypertensive agents, the reported prevalence of aldosteronism was approximately 20%. These results are consistent with a study from separate investigators reporting a prevalence of aldosteronism of 17% among subjects referred to hypertension specialists for uncontrolled hypertension. Thus, PA should be excluded in all patients in whom secondary hypertension is suspected.

Sodium Ingestion—Volume Overload

An increased salt sensitivity may be a cause of refractory hypertension. There is a subset of patients who are more likely to manifest increased salt sensitivity, including blacks, the elderly, and patients with underlying renal insufficiency. In any patient, excessive sodium intake can blunt the antihypertensive benefit of most agents. With the exception of calcium channel blockers (CCBs), antihypertensive drugs show greater effectiveness when the patient follows a low sodium diet. Also, treatment with vasodilators or adrenergic blockers can favor an expansion of volume and resistance to the treatment (pseudoresistance). When a volume overload is suspected, 24-hour measurement of sodium urinary excretion can be insufficient to determine sodium intake. The quantification of total plasmatic volume can provide reliable information about the degree of volume overload, and can serve as a guide at the time of prescribing a diuretic.

Special Tests and Examinations

The auscultatory method of BP measurement with a properly calibrated and validated instrument should be used. Patients should be seated and should relax for at least 5 minutes in a chair rather than on an examination table, with feet on the floor and arm supported at heart level. Measurement of BP in the standing position is indicated periodically, especially in those at risk for postural hypotension. An appropriate-sized cuff bladder (encircling at least 80% of the arm) should be used to ensure accuracy. At least two measurements should be made.

The readings should take place in a calm environment, after a rest time of 5–15 minutes, at least 30 minutes after the consumption of stimulants such as coffee or tobacco, since nicotine as much as caffeine can temporarily elevate BP readings. However, the possible alertness reaction that may take place during the consultation limits BP readings and contributes to an increase in the prevalence of uncontrolled hypertension. The use of a correct technique with several consecutive measurements (especially by nurse personnel) offers results comparable to ambulatory measurements and provides a better evaluation of hypertensive patients. When ambulatory BP monitoring (ABPM) is used, 20–50% of patients previously diagnosed with high BP display normal BP values. Noninvasive, 24-hour ABPM has evolved over the past 25 years from a novel research tool of limited clinical use to an important and useful modality for stratifying cardiovascular risk and guiding therapeutic decisions. Early clinical uses of ABPM mostly focused on identifying patients with white-coat hypertension; however, growing evidence now points to greater prognostic significance in determining risk for hypertensive end-organ damage compared with office BP measurements. Ambulatory measurement of BP using automated devices has demonstrated the benefit in treatment resistance and borderline hypertension, and is recommended by the Joint National Committee for the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure in a number of clinical scenarios.

On the other hand, self-measurement of BP (SMBP) at the patient's home with the correct technique and a valid and properly calibrated digital device provides very useful information on BP values of everyday life. The potential advantages of having patients take their own BP are two-fold: The distortion produced by the white-coat effect is eliminated, and multiple readings can be taken over prolonged periods of time. SMBP plays an increasing role in the diagnosis of hypertension. It may be used as a first step in the evaluation of patients with suspected white-coat hypertension, as recommended in JNC 7. There is also evidence that SMBP can improve BP control.

Pseudohypertension is another factor that can lead to a false misdiagnosis of refractory hypertension when intra-arterial pressures are actually normal or below normal. It refers to the phenomenon whereby vascular stiffening results in falsely high auscultatory BP measurements. Some studies suggest that pseudohypertension may be common among the elderly, but definitive evaluation is lacking. Pseudohypertension might be suspected if some of the following occur:

1. Severe hypertension in the absence of demonstrable target-organ deterioration.

2. Symptoms of hypotension in patients with seemingly resistant hypertension.

3. Radiologic evidence of calcification of the brachial artery.

4. BP values more elevated in the brachial artery than in the legs.

5. Severe isolated systolic hypertension.

The Osler maneuver (the ability to palpate the brachial or radial a rtery despite ipsilateral occlusion of the artery by a BP cuff inflated to suprasystolic values) constitutes a simple screening test for pseudohypertension. Another of value when pseudohypertension is suspected is the use of ultrasonic or oscillometric measuring instruments since their readings correlate more closely with intra-arterial pressure values than those obtained by an indirect auscultatory sphygmomanometer.

Insufficient or Inadequate Treatment

When physicians fail to prescribe lifestyle modifications, adequate antihypertensive drug doses, or appropriate drug combinations, inadequate BP control may result. Most patients with hypertension will require two or more antihypertensive medications to achieve their BP goals. The addition of a second drug from a different class should be initiated when use of a single drug in adequate doses fails to achieve the BP goal. When BP is more than 20/10 mm Hg above goal, consideration should be given to initiating therapy with two drugs, either as separate prescriptions or in fixed-dose combinations. In a review of cases of refractory hypertension in a hypertension unit, an inadequate therapeutic regime was the most frequent (43%) cause of resistance. After the corresponding adjustment in these therapeutic regimes, especially after the use of diuretics, BP came under control. CCBs and α-adrenergic receptor blockers (α-blockers) promote sodium and fluid retention, which may favor an inadequate control of BP, mainly when they are not used in combination with a diuretic. The administration of a drug with an active effect not sufficiently prolonged can bring about insufficient BP control that appears to be resistant to treatment. Likewise, the use of an inadequate drug combination, either belonging to the same pharmacologic group, or with a similar mechanism of action, or with opposing effects, can have negative consequences for obtaining adequate BP control. However, the administration of an adequate drug combination, with synergistic effects, including the administration of fixed doses, can significantly improve the observed response rates over those achieved with the use of each drug by itself.

Figure 44–1 shows a model of synergistic combinations proposed in the last European directives that can be useful in testing the adjustment of the associations.

Table 44–3 gives several recommendations for optimal pharmacologic treatment.

Poor Patient Compliance

Poor patient compliance remains the most important reason for inadequate BP control. The lack of adherence to hypertensive treatment is one of the major determinants of the excess morbidity and mortality observed in hypertensive patients, and must be taken into account in all patients with refractory hypertension. Studies have demonstrated that in some patient groups at 1 year, fewer than 30% of patients are still taking their antihypertensive medication. There are multiple factors that influence patient compliance, including education, socioeconomic status, and drug costs. There have been numerous studies concerning the reasons for the lack of adherence to treatment and how to detect it. However, direct questioning of the patient on the correct taking of the medication continues to be the most practical measure to confirm lack of adherence to treatment. In these cases, the taking of medication under the supervision of health personnel is usually accompanied by a noticeable reduction in BP, although this measurement is not regularly made. Also, the use of electronic devices to objectively monitor following of the therapeutic treatment has contributed to an awareness of standards of behavior of patients and restores more adequate measures of control. Additionally, the role of nurse personnel in support and education programs for hypertensive patients is of great importance.

The two main factors that have been shown to be most important in influencing patient compliance are the side effect profiles of the antihypertensive agents and the convenience of the dose schedule.

Adverse Events

The side effects that are associated with antihypertensive agents, as well as those perceived by patients to be associated with antihypertensive agents, remain by far the most important cause of poor patient compliance. It is thus crucial and almost always possible to find drugs or drug combinations that can be well tolerated by individual patients, and a concerted effort should be made to find the right drugs. It should be kept in mind that almost all side effects associated with antihypertensive agents are dose related, and utilizing smaller doses will frequently alleviate the side effects.

Convenience

It has been clearly demonstrated that patients who need to take antihypertensive agents twice a day take their drugs less readily than those provided with only one daily dose. Thus, wherever possible, patients should be treated with once-a-day agents. In selecting once-a-day agents, it is important to use those with a true 24-hour effect. The risk of nonembolic strokes and of myocardial infarction peaks in the early morning and coincides with the rapid surge of BP. This occurs during arousal from sleep (typically between 6 am and noon). Adequate BP control during this period seems to be associated with fewer cardiovascular events. Antihypertensive agents taken once daily in the morning that do not provide 24-hour efficacy may leave patients with no control at a time when they are at greatest risk of developing cardiovascular events. The duration of action of a particular antihypertensive drug can be assessed in the clinical setting by measuring BP at the trough of drug action (24–26 hours after dosing). Patients should omit taking their medication on the morning of the clinic visit so that BP is measured at trough. If BP is controlled, the agent is providing 24-hour coverage; if not, it should be replaced or two daily doses prescribed.

Table 44–3 summarizes some of the keys to improving adherence to treatment.

The best treatment for resistant hypertension is based on identification and reversal of contributing factors. Accordingly, it is mandatory to make a thorough search for noncompliance to treatment and to evaluate the adequacy of the treatment regimen, drug interactions, and associated conditions (Figure 44–2). Noninvasive, 24-hour ABPM may be an important and useful modality for identifying patients with white-coat hypertension. In the absence of the above factors, assessment for secondary causes of hypertension, in particular hyperaldosteronism, is appropriate.

Addition of low-dose spironolactone (12.5–50 mg) was associated with a mean decrease in BP of 21 ± 20 mm Hg/10 ± 14 mm Hg at 6 weeks and 25 ± 20 mm Hg/12 ± 12 mm Hg at 6-month follow-up in subjects with resistant hypertension. The reduction in BP was similar to subjects with high urinary aldosterone excretion and normal or low aldosterone excretion. Also, spironolactone lowered BP equally in African-American and white subjects. These results demonstrate that an aldosterone antagonist can be effective in treating hypertension resistant to multidrug regimens that include a diuretic and an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Additional reduction in BP was also achieved in subjects without hyperaldosteronism. Benefits in such subjects may have been secondary to additional diuretic effects of the aldosterone antagonist or may reflect a broad role of aldosterone in causing resistant hypertension even in the absence of demonstrable hyperaldosteronism. Recent clinical trials document the efficacy of eplerenone, a selective aldosterone antagonist, in treating hypertension in subjects with primary hypertension. Eplerenone would likewise be effective as an additional therapy in subjects with resistant hypertension while avoiding the antiandrogenic and antiprogesteronic effects of spironolactone. Studies evaluating eplerenone specifically in this setting are warranted.

With an aging and increasingly obese population, the prevalence of resistant hypertension will undoubtedly increase. Even now, failure of multidrug regimens of three or more medications to control BP is common. Aldosterone antagonists can provide significant reductions in BP in these difficult-to-treat patients. Hyperkalemia or acute renal insufficiency occurs rarely, and should be monitored for, particularly in patients with chronic kidney disease and/or diabetes.

The general benefit of an aldosterone blockade in subjects with resistant hypertension suggests that aldosterone excess may be a more common cause of hypertension than previously thought. However, the aldosteronism that we are reporting as being so common is undoubtedly different from the classic syndrome of primary aldosteronism. The regulatory abnormalities, distinct from classic aldosteronism, resulting in such a high prevalence of aldosteronism are unknown. Recognition of such abnormalities may allow prevention and/or development of even more effective treatment strategies.

Truly refractory hypertension, hypertension in which all known refractory causes can be excluded, could become a rarity. Nonetheless, from a practical point of view we offer a series of steps to detect, control, or diminish the conditioning factors, emphasizing the need to arrive at a correct diagnosis. For this diagnosis, the basic pillars are an adequate measuring of pressure, a guarantee of correct associations, an acceptable carrying out of the prescribed regime, and, lastly, ruling out secondary forms of hypertension. Arriving at this point, the intervention of a specialist can ensure the control of BP by means of the combined use of four or more antihypertensive agents.