• 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.