Hypertension is the most common chronic disease in developed societies, affecting >25% of adults (1). Meta-analyses have demonstrated a linear relationship between level of blood pressure (BP) and risk for cardiovascular events (2- 4). Suboptimal BP control is, consequently, the most common attributable risk for death worldwide, being responsible for 62% of cerebrovascular disease and 49% of ischemic heart disease as well as an estimated 7.1 million deaths a year (5).

In the U.S., both the net and age-adjusted prevalence ratios of hypertension continue to increase. Recent data suggest, however, a slight improvement in hypertension awareness, treatment, and control (6). The rates of hypertension treatment and control in Europe are much lower than in the U.S. (7). Several large hypertension outcome trials also demonstrate a failure to achieve BP goals in spite of protocol-defined treatment regimens. In these trials, 20% to 35% of participants could not achieve BP control despite receiving >3 antihypertensive medications (8- 10) (Figure 1).

This article provides the clinician with an overview of the patient characteristics associated with resistant hypertension, the diagnostic evaluation to assess the problem, and the treatment strategies for optimizing BP control.

The Joint National Committee 7 defines resistant hypertension as failure to achieve goal BP (<140/90 mm Hg for the overall population and <130/80 mm Hg for those with diabetes mellitus or chronic kidney disease) when a patient adheres to maximum tolerated doses of 3 antihypertensive drugs including a diuretic (11). This definition does not apply to patients who have been recently diagnosed with hypertension (12). Moreover, resistant hypertension is not synonymous with uncontrolled hypertension. The latter includes all hypertensive patients who lack BP control under treatment, namely, those receiving an inadequate treatment regimen, those with poor adherence, and those with undetected secondary hypertension, as well as those with true treatment resistance. By this definition, patients with resistant hypertension may achieve BP control with full doses of 4 or more antihypertensive medications (13- 14). Although the definition of resistant hypertension is arbitrary relative to the number of antihypertensive medications required, the concept of resistant hypertension is focused on identifying patients who are at high risk of having reversible causes of hypertension and/or patients who, because of persistently high BP levels, may benefit from special diagnostic or therapeutic considerations (13).

The prevalence of resistant hypertension in the general population is unknown because of an inadequate sample size of published studies as well as the feasibility of doing a large enough prospective study that would answer the question (15- 16). Small studies, however, demonstrate a prevalence of resistant hypertension that ranges from ≈5% in general medical practice to >50% in nephrology clinics (15).

Based on data from the National Health And Nutrition Examination Survey, 2003 to 2004, 58% of people being treated for hypertension achieve BP levels <140/90 mm Hg (6); control rates among those with diabetes mellitus or chronic kidney disease are <40% (6,17). In Europe, the situation is worse, with control rates among treated hypertensive patients between 19% and 40% in 5 large countries (7). Such data suggest that resistant hypertension is more common than appreciated; however, accurate estimates are not possible, as control rates under treatment are affected by many factors.

There are no studies specifically powered to address the prognosis of persons with resistant hypertension. However, as evident from all population studies on hypertension-related target-organ damage, the risks of myocardial infarction, stroke, heart failure, and renal failure directly relate to the level of BP (3,11).

These observations coupled with the most common comorbid conditions seen in patients with resistant hypertension, namely, obesity, diabetes, or chronic kidney disease, translate into an unfavorable prognosis if the BP goal is not achieved (13). The extent of cardiovascular morbidity and mortality reduction with achievement of the BP goal has not been evaluated; however, the benefits are evident by results of major outcome studies (2,11,18- 19).

The term “pseudo-resistance” refers to lack of BP control with appropriate treatment in a patient who does not have resistant hypertension. Several factors contribute to elevated BP readings and produce the perception of resistant hypertension (12- 16) (Table 1). Such factors include the following: 1) suboptimal BP measurement technique; 2) the white-coat effect; and 3) poor adherence to prescribed therapy and other causes described in the following text (13- 14). A careful evaluation to exclude these factors before labeling someone as having resistant hypertension should be performed.

Although guidelines to properly assess office BP are widely available (20), several common mistakes often produce falsely elevated BP readings. Such mistakes include not allowing the patient to sit quietly for adequate time, taking single instead of triple readings, using cuffs that are too small for the arm, recent smoking, and not fully supporting the arm at heart level (12- 13,16). In older patients, the presence of heavily calcified or arteriosclerotic arteries that cannot be fully compressed is common and results in overestimation of intra-arterial BP (12,16).

The “white-coat effect,” defined as an elevation of BP during a clinic visit resulting in higher office readings than at home or ambulatory BP readings (21), is another cause of pseudo-resistance. The white-coat effect is common among patients with perceived resistant hypertension; ≈25% of such patients referred for resistant hypertension achieve goal BP under treatment when ambulatory measurements are performed (22). Patients with apparent resistant hypertension due to the white-coat effect have less target-organ damage compared with truly resistant hypertensive patients (23- 24). Therefore, such patients should have home or ambulatory BP measurements (12).

Poor adherence to an adequate antihypertensive regimen is another cause of apparent resistant hypertension. Studies suggest that up to 40% of newly diagnosed hypertensive patients will discontinue their antihypertensive medications during the first year, with only 40% of the remaining patients continuing their therapy over the next decade (25- 27). An evaluation of 4,783 hypertensive patients enrolled in phase IV clinical studies, with follow-up ranging from 30 to 330 days, demonstrated a discontinuation rate of antihypertensive drug of ≈50% within 1 year (28). Moreover, there was an inverse relationship between the likelihood of early treatment discontinuation and the frequency of the daily dosing regimen. Factors that improve medication adherence include the following: 1) selection of agents with low side effect profiles such as blockers of the renin-angiotensin system (RAS); 2) avoidance of complicated dosing schedules so that once-daily agents either alone or in fixed dose would be preferred; 3) use of pill boxes or family to help patients with memory deficits or psychiatric disorders; and 4) improved communication between the patient and physician to ensure that the patient understands the regimen and why the medication should be taken in the way prescribed. Failing to educate the patient about the importance of achieving BP goals, the predicted side effects of the agents, and the cost of medication are the most common reasons for drug discontinuation (29- 30).

A relatively surprising cause of pseudo-resistant hypertension is suboptimal dosing of antihypertensive agents or inappropriate combinations of agents. Data from a clinical hypertension specialty clinic demonstrated that either increasing the dose or initiating or switching to the proper diuretic was the most common change that achieved BP goal among patient referred for resistant hypertension (31).

An important culprit that contributes to the genesis of pseudo-resistant hypertension is clinical inertia, defined as the conscious decision by a clinician to not adequately treat a condition despite knowing that it is present (32). Despite efforts to translate evidence-based guidelines into clear recommendations for clinical practice (11), many physicians are reluctant to adhere to these guidelines (16). Clinical inertia may be due to lack of training and experience in the proper use of antihypertensive agents or an overestimation of care already provided (33). Several studies (34- 35) suggest that this phenomenon is frequent among American physicians and represents an important culprit working against the efforts to improve hypertension control rates in the population.

Reasonable algorithms to identify people with pseudo-resistant hypertension have been proposed (12- 13). In general, these approaches adopt a 2-step approach: first, confirmation of true resistance (by simultaneous recognition and correction of factors related to pseudo-resistance); and second, identification of the factors that contribute to treatment resistance in a given patient (Table 2).

The first step to rule out resistant hypertension is confirmation of the diagnosis with reliable office BP readings; the observer should strictly follow the relevant BP measurement guidelines (20). Particular attention should be paid to the patient's posture, environment, and triple BP readings with adequate intervals between. Additionally, use of appropriate cuffs and devices is mandatory. Adherence to the recommended BP measurement technique will uncover patients who do not meet the definition of resistant hypertension.

Identification of patients who have the white-coat effect is also important. Either having qualified nonphysician personnel (i.e., nurses) perform office measurements or using an automated device with the patient alone in the room is useful. Of greater importance, however, is the determination of BP levels under treatment with home or ambulatory measurements, again following relevant recommendations (20,36). If BP remains elevated after this evaluation, patient adherence to therapy should be evaluated, as noted earlier.

Apart from the aforementioned variables, a number of biological or life-style factors can contribute to the development of resistant hypertension. Several classes of pharmacological agents can produce transient or persistent increases in BP (37) (Table 3). Nonsteroidal anti-inflammatory drugs (NSAIDs) are a common cause of worsening BP control. They increase BP by an average of 5 mm Hg, in part because of inhibition of renal prostaglandin production decreases in renal blood flow, followed by sodium and fluid retention (38). They also interfere with BP-lowering of all antihypertensive drug classes except calcium antagonists (39- 40). The effect of NSAIDs on BP is more pronounced in patients with reduced kidney function (13). Selective cyclo-oxygenase-2 inhibitors have effects similar to those of NSAIDs on BP control (41). Sympathomimetic agents (nasal decongestants, anorectic pills, cocaine, amphetamine-like stimulants), oral contraceptives, glucocorticoids, anabolic steroids, erythropoietin, and cyclosporine are also commonly used agents that can interfere with BP control. Black licorice, included in some oral tobacco products, and herbal supplements (e.g., ma huang and ginseng), also raise BP (12- 13,16). The effect of these agents varies; most people manifest little or no effect, but certain persons may experience severe BP elevations. Lastly, illicit drugs can be a major unappreciated cause of resistant hypertension. Agents such as steroids and cocaine are common causes of resistant hypertension.

Although modest alcohol consumption does not generally increase BP, larger amounts (3 or more drinks/day) have a dose-related effect on BP, both in hypertensive and normotensive persons (11). Alcohol intake in all hypertensive patients should be limited to no more than 1 oz of ethanol a day in most men (the equivalent of 2 drinks) and 0.5 oz of ethanol a day in women and lower-weight persons (11).

A key factor responsible for many cases of resistant hypertension is excess dietary salt intake leading to volume overload (16). Data from small studies demonstrate that 90% of patients with resistant hypertension have expanded plasma volume (42). Excessive dietary sodium intake is widespread in the U.S. and other developed countries, with processed foods being the most common source (13,16). The majority of patients with resistant hypertension have higher salt intake than the general population, with an average dietary sodium intake exceeding 10 g/day (43).

The optimal way to assess sodium intake is to measure sodium excretion in a 24-h urine collection. Dietary salt reduction to <3 g/day is associated with modest BP reductions, which are larger in African-American and elderly patients (44). Current guidelines suggest that dietary sodium for a hypertensive person should be <100 mmol/day (2.4 g sodium or 6 g sodium chloride) (11). This guidance is applicable to all patients with resistant hypertension, whereas for salt-sensitive patients, even lower amounts of sodium may be necessary.

Perhaps the most common unappreciated medical cause of resistant hypertension is the presence of renal parenchymal disease. Kidney disease is the most common secondary medical cause of hypertension. Failure to appreciate this relationship may lead to less than optimal choices of antihypertensive agents such as failure to use appropriately dosed or selected diuretics based on kidney function. This lack of diuretic use has been shown in referral practices to be the primary cause of resistant hypertension, with the use of these agents helping to achieve BP goals (31).

Obesity is also a very common feature of patients with resistant hypertension (45- 46). The mechanisms by which obesity contributes to BP elevation and interferes with BP control are complex and not fully understood. Insulin resistance and hyperinsulinemia, impaired sodium excretion, increased sympathetic nervous system activity, increases in aldosterone sensitivity related to visceral adiposity, and obstructive sleep apnea have all been implicated as potential causes (47- 49).

Weight loss achieved with both an appropriate exercise program and a reduced calorie diet is associated with modest BP reductions in obese hypertensive patients (12- 13). These reductions are greater in patients already receiving antihypertensive therapy (50).

Increasing age, namely, >65 years old, is associated with a higher prevalence of resistant hypertension (16,51). Increasing age is associated with a higher prevalence of arterial stiffening, which is not only responsible for falsely elevated systolic BP readings but also a major cause of true elevations (11,16). Current guidelines for systolic BP goals of <140 mm Hg are more difficult to achieve in patients with isolated systolic hypertension (11) and are more difficult with increasing age because of the natural history of arteriosclerosis.

Finally, in patients with resistant hypertension, the presence of secondary hypertension must be considered; although its prevalence is largely unknown, previous studies have shown that ≈5% to 10% of patients with resistant hypertension have an identifiable cause (52- 53). As already mentioned, renal parenchymal disease must be considered with the strict sense as the most common medical cause of secondary hypertension (12,16). Renal arterial disease, primary aldosteronism, and obstructive sleep apnea are other common identifiable causes, whereas less common forms of secondary hypertension include pheochromocytoma, Cushing's syndrome, hyperparathyroidism and hypoparathyroidism, aortic coarctation, and intracranial tumors (Table 3). The possibility of an identifiable cause of hypertension increases with age: renal disease, sleep apnea, and possibly primary aldosteronism are more prevalent among older patients (13,54).

Patients with documented resistant hypertension should be evaluated for secondary hypertension if indicated by clinical and routine laboratory evaluation (11). Description of the signs and symptoms, diagnostic procedures, and treatment of identifiable causes of hypertension is beyond the scope of this article (13).

Suboptimal dosing regimens or inappropriate antihypertensive drug combinations are the most common causes of resistant hypertension (52- 53). Recommendations on the modification and intensification of antihypertensive regimens for a given patient taking 3 or more drugs is based on pharmacological principles in the context of the underlying pathophysiology that portends hypertension, clinical experience, and available treatment guidelines.

The present rationale for intervention in resistant hypertension (Figure 2) is to ensure that all possible mechanisms for BP elevation are blocked. As volume expansion seems the most frequent pathogenic finding in these patients (42,55), an appropriate diuretic to decrease volume overload remains a cornerstone of therapy (12,16,56). Studies suggest that changes in diuretic therapy (adding a diuretic, increasing the dose, or changing the diuretic class based on kidney function) will help >60% of these patients achieve BP goals (12,42,53,55- 57). Thiazide diuretics are effective from doses of 12.5 mg/day given that kidney function is normal; increases up to 50 mg may provide additional BP reduction in some patients (12). Of note, there are differences between thiazide and thiazide-type diuretics (13- 14,58). A recent trial comparing hydrochlorothiazide 50 mg and chlorthalidone 25 mg daily demonstrated that the latter provided greater ambulatory BP reduction, with the largest difference occurring overnight (59). Additionally, a small study of patients with resistant hypertension demonstrated that switching from the same dose of hydrochlorothiazide to chlorthalidone resulted in an additional 8 mm Hg drop in systolic BP and increased the number of subjects at goal (60). Unfortunately, chlorthalidone is not commonly available in fixed-dose combinations; therefore, its use will require separate prescriptions.

The most crucial part of diuretic therapy is to know when kidney function has deteriorated, so that one may select the proper class of diuretic. For thiazides, this deterioration is generally thought to have occurred when the estimated glomerular filtration rate (eGFR) falls to <50 ml/min/1.73 m²; chlorthalidone can still be effective to an eGFR of ≈40 ml/min/1.73 m² if hypoalbuminemia or hyperkalemia is not present. For patients with eGFR <40 ml/min/1.73 m², a loop diuretic should be used (12- 13,16). Furosemide or bumetanide must be given twice daily, and possibly thrice daily in some cases, as they have short durations of action of 3 to 6 h. Thus, once-daily use is associated with intermittent natriuresis and consequent reactive sodium retention mediated by increases in the RAS (12,16,61). The loop diuretic torsemide has a longer duration of action and may be given once or twice daily (12).

Use of the other drug classes in patients with resistant hypertension should be based on the general principles of combination therapy, namely, inhibition of different pathogenic mechanisms, choice of drugs that will compensate for possible pathophysiological changes evoked by the first drug, and consideration of compelling indications (11- 12). Moreover, the Food and Drug Administration has recently approved 3 fixed-dose combination antihypertensive agents for use as first-line therapy (62). These combinations all have an agent that blocks the RAS. Fixed-dose antihypertensive combinations are also very useful for patients with resistant hypertension, especially for those with adherence problems (63- 64).

Ultimately, patient characteristics (age, probable pathogenic mechanisms involved, and concomitant diseases) will determine the best combination of agents needed to achieve BP goal. In general, most patients should be on a blocker of the RAS along with a calcium antagonist and an appropriately dosed diuretic. In this case, the physician must ensure that these agents are prescribed in full dosages, especially for patients with increased weight, and for appropriate time intervals. If BP remains above goal, the next step is to add a fourth agent; a vasodilating beta-blocker is a good choice if pulse rate is not too low. Peripheral alpha-blockers are well tolerated and can be used if the beta-blocker selected does not have alpha-blocking activity.

For true resistant hypertension, there are also good data to support adding a complementary calcium antagonist to a regimen including a RAS blocker, diuretic, and calcium-channel blocker (CCB); for example, adding long-acting diltiazem to nifedipine XL. Such a combination of complementary CCBs results in additive BP reduction with a low side effect profile and makes pharmacological sense (65- 66).

Combining an angiotensin-converting enzyme (ACE) inhibitor with an angiotensin receptor blocker (ARB) does not make sense as it was recently shown to be less effective in terms of BP reduction than was adding a diuretic or a CCB to an ARB (67), was shown not to reduce cardiovascular or renal events to any greater extent than individual agents, and may confer increased risk of side effects (68- 69). In a separate trial, the combination of a renin inhibitor (aliskiren) with an ARB was also associated with a small additional BP drop (70). Thus, dual RAS blockade is not recommended for patients with resistant hypertension.

Aldosterone is also part of the RAS, and specific blockade of aldosterone should be considered in certain settings. Recent studies suggest that adding spironolactone or eplerenone to existing antihypertensive regimens for patients with resistant hypertension who are obese or have sleep apnea provides significant BP reduction (13,71). For 76 patients with uncontrolled BP taking an average of 4 antihypertensive medications, the addition of spironolactone (12.5 to 25 mg daily) resulted in an average 25/12 mm Hg reduction after 6 months (72). Reductions in BP were similar in patients with and without primary aldosteronism and were not predicted by baseline plasma or 24-h urinary aldosterone, plasma renin activity, or plasma aldosterone/renin ratio. These data were confirmed by a recent report of 1,411 participants in the Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm who were unselected for plasma aldosterone and renin activity (73) and who received spironolactone as a fourth-line antihypertensive agent for uncontrolled BP in addition to an average of 3 drugs. Use of spironolactone resulted in a BP drop of 21.9/9.5 mm Hg that was unaffected by age, sex, smoking, and diabetic status. Breast tenderness with spironolactone is common at doses above 25 mg/day but can be avoided with the use of the more selective mineralocorticoid receptor antagonist, epleronone (14). Epleronone also has demonstrated BP-lowering efficacy as well as benefits on kidney disease progression (74).

Amiloride is another potassium-sparing diuretic associated with BP reductions in patients with resistant hypertension (75). When physicians prescribe these agents, especially in combination with an ACE inhibitor or an ARB, they should monitor potassium levels closely if kidney function is not within the normal range, and educate the patient to avoid food and supplements rich in potassium, as hyperkalemia is a potentially dangerous side effect (14,76).

If BP control is still not achieved with full doses of a 4-drug combination, use of other agents such as centrally-acting alpha-agonists (methyldopa and clonidine) or vasodilators (hydralazine or minoxidil) is needed. These agents are very effective for lowering BP, but have poor tolerability and lack of positive outcome data (11). It must be noted, however, that if therapy has progressed to adding a fourth agent, referral to a clinical hypertension specialist is warranted (33).

Another class of agents that may prove useful for resistant hypertension is endothelin-receptor antagonists (ERAs). In patients with mild-to-moderate essential hypertension, both nonselective and selective (type A receptor) ERAs produce BP reductions comparable to those of common antihypertensive agents (77), but concerns about adverse events precluded their use as a treatment option for uncomplicated hypertension (78). However, darusentan, a selective ERA recently tested in 115 patients with resistant hypertension, demonstrated a dose-dependent decrease in BP. The largest reductions (11.5/6.3 mm Hg) were observed after 10 weeks of follow-up with the largest dose, and the drug was generally well tolerated (78). Ongoing phase III clinical trials with such agents are awaited to provide further information in this interesting field.

Although the number of patients who cannot achieve BP goals on a regimen of multiple medications is growing, the phenomenon of resistant hypertension is widely understudied, a fact that requires treatment recommendations be based on pathophysiological principles and clinical experience. Effective management of resistant hypertension requires, first, a careful examination for and exclusion of factors associated with pseudo-resistance, and second, identification and, when possible, modification of factors related to true BP elevations. After all of these are successfully managed, an aggressive treatment regimen designed to compensate for all mechanisms of BP elevation in a given patient, most importantly to control volume overload with proper use of diuretics, will help in moving toward effective BP control for the majority of patients.