Abstract

Resistant hypertension is defined as blood pressure (BP) that remains above goal (such as 140/90 mmHg or more) in spite of the concurrent use of three antihypertensive agents of different classes. Ideally, one of the three agents should be a diuretic and all agents should be prescribed at optimal dose amounts. Prevalent among 15% of the treated hypertensives, the risk factors for resistant hypertension include older age, chronic kidney disease (CKD), obesity and diabetes mellitus. Causes of resistant hypertension can be classified into four groups: poor adherence, biological–behavioral factors, CKD and secondary causes, and drugs or exogenous substances. However, before labeling the diagnosis of resistant hypertension, it is important to exclude pseudo-resistant hypertension using home BP monitoring in most patients and ambulatory BP monitoring in a few. Before thinking about the next antihypertensive drug, it is important to restrict dietary sodium. Educating the patient on how to interpret the food label and providing feedback by assessing sodium intake with 24 h urine collection are effective sodium restriction strategies. Sodium restriction can lower BP and among patients with proteinuria can even enhance the anti-proteinuric effects of drugs that block the renin–angiotensin system. Sodium restriction is therefore a valuable but a neglected antihypertensive.

Resistant hypertension: definitions and epidemiology

According to the definition endorsed by the American Heart Association, resistant hypertension is defined as blood pressure (BP) that remains above goal (such as 140/90 mmHg or more) in spite of the concurrent use of three antihypertensive agents of different classes [1]. Ideally, one of the three agents should be a diuretic and all agents should be prescribed at optimal dose amounts.

Resistant hypertension is common. Among adults treated with antihypertensive drugs in the US National Health and Nutrition Examination Survey (NHANES) performed between 2005 and 2008, resistant hypertension was noted in 12.8% [2]. As a fraction of the overall hypertensive population, the prevalence of resistant hypertension was 8.9%. Thus, the number of hypertensive people in the USA who have resistant hypertension is estimated to be ∼6 million. As a cause of poorly controlled hypertension, therapeutic inertia may be more common than resistant hypertension. Of the patients who were poorly controlled, 72.4% were taking only one to three antihypertensive medications. Although the use of diuretics among patients with uncontrolled hypertension was 85.6%, the dose may have been inadequate or the choice of the diuretic may have been inappropriate [2].

The prevalence of resistant hypertension is increasing [3]. Among 13 375 hypertensive adults who participated in the NHANES, the percentage of patients who took three antihypertensive medications or more and were poorly controlled was 6.5% in 1988–94, 9.3% in 1999–2004 and 13.4% in 2005–08 [3]. The percentage of hypertensive patients who were left untreated declined from 59.0% in 1988–94, 56.1% in 1999–2004 and 52.2% in 2005–08 [3]. However, the prevalence of treated patients who took three antihypertensive medications or more and were poorly controlled increased from 15.9% in 1988–94, 21.2% in 1999–2004 and 28.0% in 2005–08 [3]. Resistant hypertension in the NHANES survey (2005–08) was independently associated with older age, black race, obesity, chronic kidney disease (CKD), an elevated CHD risk (>20% at 10 years) and frequent healthcare visits (4 or more per year) [3].

Some estimates of the prevalence of resistant hypertension can be derived from recent trials because of the need to force titrate drugs to achieve BP control. From these trials that have a large number of patients with multiple morbidities, it is estimated that 35–50% of the participants may have resistant hypertension [4].

The incidence of resistance hypertension was evaluated in a large retrospective study from a managed health organization in US, Kaiser Permanente [5]. Incident hypertension was defined as elevated BP based on Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure thresholds with lower BP thresholds for diabetes mellitus or CKD (130/80 mmHg). After diagnosis of hypertension, patients were followed if they were ever given at least one antihypertensive drug. Patients taking three or more classes of antihypertensive drugs for at least 1 month were divided into two groups: controlled or uncontrolled hypertension based on their BP. Next, the study cohort patients taking at least three medications were followed up for 1 year to assess hypertension control based on the BP measurement closest to 1 year after they started taking three antihypertensive medications and to assess adherence to antihypertensive medications. Among those in whom hypertension was controlled at 1 year, those taking four medications were considered resistant and those taking <3 medications were considered non-resistant. Among those in whom BP was not controlled at 1 year, those taking up to three medications were considered non-resistant and those taking three or more medications were considered resistant.

Of the ∼200 000 patients with incident hypertension, ∼42 000 (21%) were prescribed at least three medications which they took for at least 1 month. Further data were available on ∼25 000 participants. At baseline, ∼25% had BP controlled. Of those with controlled hypertension, at the end of the year, ∼75% remained controlled. Of the remaining 25% with poor control, only ∼25% were resistant. The vast majority were not treated adequately (therapeutic inertia) and a small fraction (<4%) were non-adherent. At baseline, poor control of BP was present in 75%. Of these, 55% had BP well controlled at 1 year. Since 7% of the latter needed at least four medications, they had resistant hypertension. Forty-five percent had poor control of BP at 1 year. Of the latter, the distribution of hypertension was as follows: resistant hypertension was present in 38%, non-adherence in 5% and therapeutic inertia in 56%. Overall, the annual incidence of resistant hypertension was 1.9% of the incident hypertensive population. Since 3801 patients of the initial 24 499 patients who required at least three antihypertensive drugs at baseline had resistant hypertension, the incidence of resistant hypertension in this more meaningful group was 15.5%.

One has to reconcile the low overall incidence of resistant hypertension (<2%) with overall prevalence of 12.8% by one estimate [2], 15.5% in another [5] and 28.0% [3] in a third study. Furthermore, the prevalence of resistant hypertension has increased 1.8-fold over two decades [3]. Since the number of untreated patients has declined [3], the intensity of treatment has likely increased over the same period. By definition, increased use of antihypertensive therapy would increase the prevalence of resistant hypertension. Although resistant hypertension is deemed to increase cardiovascular risk [5], current data suggest that this risk is largely driven by incident CKD. Better care of CKD and increased survival of these patients may elicit an increase in the prevalence of resistant hypertension.

Resistant hypertension has many causes. Truly resistant hypertension can be classified into four major categories (Table 1): non-adherence to therapy; biological and behavioral factors (examples of which include older age, excess sodium intake, obesity and smoking); CKD and other secondary causes of hypertension (such as aldosteronism, diabetes mellitus and sleep apnea) and drugs either prescribed (cyclosporine, erythropoietin, NSAIDs) or recreational (for example cocaine). Although some regard non-adherence as pseudo-resistant hypertension, adherence is difficult to assess by medication possession [5]; accordingly, non-adherence should be considered as a cause of resistant hypertension. Nonetheless, before we label the diagnosis of resistant hypertension, it is important to exclude pseudo-resistant hypertension. It should be noted that despite being pseudo-resistant, these patients likely have cardiovascular risk that is many times that of true normotensives.

Table 1.

Causes of resistant hypertension (ABCD)

A. Non-adherence to therapy 
B. Biological and behavioral factors 
 Older age 
 Excess sodium intake 
 Low potassium intake 
 Obesity 
 Smoking 
C. Chronic kidney disease and other secondary causes of hypertension 
 Aldosteronism 
 Diabetes mellitus 
 Sleep apnea 
D. Drugs 
 Prescribed (e.g. cyclosporine, erythropoietin, NSAIDs) 
 Recreational (e.g. cocaine) 
A. Non-adherence to therapy 
B. Biological and behavioral factors 
 Older age 
 Excess sodium intake 
 Low potassium intake 
 Obesity 
 Smoking 
C. Chronic kidney disease and other secondary causes of hypertension 
 Aldosteronism 
 Diabetes mellitus 
 Sleep apnea 
D. Drugs 
 Prescribed (e.g. cyclosporine, erythropoietin, NSAIDs) 
 Recreational (e.g. cocaine) 

Pseudo-resistant hypertension.

Pseudo-resistant hypertension is diagnosed by above threshold BP in the clinic but at goal BP outside the clinic. Although the gold standard for out-of-clinic BP monitoring is by ambulatory BP recording, home BP can serve as an effective way to screen those who may need ambulatory BP monitoring [6]. Home BP of 136/86 mmHg is considered hypertensive. If home BP is <125/75 mmHg, then patient may be considered a true normotensive and no ambulatory BP monitoring is needed. If BP is >135/85, then true hypertension is diagnosed. However, the gray zone between 125–135 and 75–85 mmHg requires further evaluation with ambulatory BP monitoring [6]. It is in these patients that ambulatory BP can discriminate between hypertensive and normotensive better than home BP monitoring.

A large Spanish registry of ambulatory BP recording evaluated 68 045 patients and found that 8295 (12%) of these patients taking three drugs or more had clinic BP of 140/90 mmHg or more [7]. Thus, these patients in the absence of further BP recordings would be labeled as resistant hypertensives. However, when these patients underwent ambulatory BP monitoring, it was found that 37.5% of these people had pseudo-resistant hypertension [7]. In other words, they simply had white coat effect. Thus, one in three patients will be wrongly classified as resistant hypertension in the absence of out-of-clinic BP monitoring. Given that office BP has no prognostic value but ambulatory BP is a strong predictor of cardiovascular morbidity and mortality in resistant hypertension [8], this finding is important for treating physicians and trialists alike. True resistant hypertension is more likely to respond to therapy than pseudo-resistant hypertension.

Dietary sodium intake and its role in resistant hypertension

Increased dietary sodium intake in modern societies is an important and treatable cause of hypertension. A meta-analysis combining results of 50 studies shows that 78 mmol/day (1.8 g) reduction in dietary sodium is associated with a reduction in BP among hypertensive people of 5.0/2.7 mmHg [9]; among non-hypertensives, BP is reduced by 2.0/1.0 mmHg [9]. Among children, a similar meta-analysis suggests lowering of BP by 1.2/1.3 mmHg [10].

In the Dietary Approaches to Stop Hypertension (DASH) randomized controlled trial, the sodium intakes in the three levels of dietary sodium prescriptions led to intakes of sodium of ∼150, 100 and 65 mEq/day [11]. Compared with the highest sodium intake, BP was reduced 2.1 mmHg systolic with moderate (100 mEq/day) sodium restriction. Compared with the highest sodium intake, BP was reduced 6.7 mmHg systolic with greater (65 mEq/day) sodium restriction. The greatest reductions in BP were seen among blacks, women and those with hypertension.

To lower the incidence of hypertension, the Institute of Medicine now recommends that dietary sodium should be restricted to <1500 mg/day (65 mmol/day) [12]. However, the intake of sodium between 1988 and 1994 was 2900–4300 mg/day or two to three times recommended. More recent estimates (2005–06) suggest that the average man in the USA consumed 4 g sodium; the average woman 2.8 g/day [13]. Statistical simulations suggest that reducing dietary sodium intake by 1200 mg/day can lead to substantial reduction in coronary heart disease, stroke, myocardial infarction and all-cause mortality [13]. These reductions would be more cost-effective than treating with antihypertensive drugs [13]. Dietary sodium restriction is also recommended as an initial step to treat pre-hypertension and Stage I hypertension. Data are now emerging that even people with later stage hypertension including those being treated with multiple antihypertensive agents such as those with resistant hypertension can benefit with this strategy.

Since most sodium intake comes from processed food, and only ∼10% from table salt, it is important to educate the patient to read food label. Even the fast food restaurants can provide information about the sodium content of their food and often have low-sodium options. To assess adherence to low-sodium diet, requires the collection of 24-h urine for sodium and creatinine. In an adequately collected sample, dietary sodium excretion of >65 mmol/day suggests >1500 mg sodium intake/day. Better response to the existing antihypertensive drugs can be expected if such patients lowered their dietary sodium intake.

Only a few studies are available that have restricted sodium intake among patients with resistant hypertension.

Pimenta et al. [14] performed a randomized cross-over trial of dietary salt restriction on office and 24-h ambulatory BP in subjects with resistant hypertension. Twelve subjects with resistant hypertension were given a low- (50 mmol/24 h × 7 days) and high-sodium diets (250 mmol/24 h × 7 days) separated by a 2-week washout period. At baseline, subjects were on an average of 3.4 antihypertensive medications with a mean office BP of 145.8 ± 10.8 systolic and 83.9 ± 11.2 mm Hg diastolic. The mean urinary sodium excretion were ∼50 mmol versus 250 mmol/24 h during low- versus high-salt intake. Low- compared with high-salt diet decreased office systolic and diastolic BP by 22.7 and 9.1 mm Hg, respectively. The reduction in ambulatory BP was similar (20.1/9.8 mmHg). Plasma renin activity increased whereas brain natriuretic peptide and creatinine clearance decreased during low-salt intake, indicative of intravascular volume reduction. Other trials have not predefined a population of resistant hypertension, but it is likely that quite a large percent had resistant hypertension and will be considered further.

Fotherby and Potter [15] performed a double-blind, randomized, placebo-controlled, crossover trial lasting 10 weeks, following a 4-week run-in period to assess the effects of 80 mmol/day reduction in dietary sodium intake on clinic and 24-h ambulatory BP in elderly hypertensive subjects. Seventeen untreated older [mean age 73 years (range 66–79)] subjects with essential hypertension [systolic BP (SBP) 160 mmHg or more and/or diastolic BP (DBP) 95 mmHg or more] had clinic BP and 24-h urinary electrolyte excretion measured while on their normal diet. Following a 4-week run-in period on a reduced sodium diet (80–100 mmol/24 h), subjects entered a 10-week crossover trial of 80 mmol/24 h sodium supplement or matching placebo while continuing on the reduced sodium diet. The mean office BP was 176/96 mmHg. There was a significant reduction in clinic supine SBP between the high- and low-sodium phases. There was a non-significant reduction (5/2 mmHg) in the mean 24-h SBP and DBP on the low-sodium intake. Overall, moderate sodium restriction in elderly hypertensives resulted in a significant fall in clinic supine SBP only, although marked differences in intersubject responses were found.

Gavras et al. [16] reported an uncontrolled trial of dietary sodium restriction (10 mmol/day × 6–14 day) and diuretics [furosemide 80–200 mg/day if CKD (n= 2) or HCTZ 100 mg] among patients with uncontrolled hypertension in maximum doses of two agents (a diuretic plus a sympatholytic). If renin–angiotensin system was not activated, spironolactone 100–300 mg was given for 4–16 days. The office BP was 176/116 mmHg at baseline, so it is quite likely that most patients had resistant hypertension. After treatment, BP fell to 155/109 mmHg (change of 21/7 mmHg from baseline). Patients with the least percent increase in PRA demonstrated the greatest fall in BP per unit of weight loss, indicating that relative activation of the renin–angiotensin system may be the factor limiting antihypertensive efficacy of sodium depletion. However, with the wide availability of renin–angiotensin aldosterone system blockers, resistance to BP-lowering effect with sodium depletion is no longer insurmountable.

CKD is a risk factor for resistant hypertension. The pharmacological effects of renin–angiotensin system blockers are enhanced when they are used along with sodium restriction. When sodium is restricted, not only is the BP reduced further, an improvement in proteinuria is also seen [17, 18].

Dialysis patients have a high prevalence of resistant hypertension. In a survey of 369 dialysis patients who had ambulatory BP recorded, four or more antihypertensive drugs were used by 59 (16%) of the patients [19]. Thus, these patients had resistant hypertension by current definition. Another 57 (15%) had three drugs being used for hypertension and the odds ratio for poor control with three drugs was 2.49 (P = 0.03). Accordingly, ∼25% of the patients on dialysis may have resistant hypertension.

Sodium restriction both dietary and in the dialysate are the cornerstones for treating resistant hypertension [20]. More importantly, volume reduction through ultrafiltration in patients consuming recommended intake of sodium is an effective way to lower BP. Since these patients are treated with multiple drugs, this is an effective strategy of controlling resistant hypertension. The volume control strategy has been tested in one randomized controlled trial [21]. The Dry-weight Reduction In Hypertensive Hemodialysis Patients (DRIP) trial randomized 150 patients in 2:1 ratio to either aggressive volume reduction or a control group [21]. Within 4 weeks, BP reduction assessed by interdialytic ambulatory BP monitoring of ∼7/3 mmHg was achieved. Despite the intake of an average of 2.5 antihypertensive drugs, this reduction in BP suggests that in this difficult to treat group, volume control was effective in providing additional antihypertensive effect. A recent analysis of the Hemodialysis (HEMO) study found an independent association of dietary sodium intake with all-cause mortality [22].

Animal studies show that dietary sodium restriction can evoke better vascular structure and function, regression of left ventricular hypertrophy and improvement in vascular inflammation and fibrosis [23–25]. Thus, dietary sodium restriction might have effects beyond BP reduction and extend to cardiovascular protection.

It is important to note that the BP-raising effects of sodium may be modulated by potassium. The mechanisms of these effects are discussed in a scholarly review by Adrogue and Madias [26]. For example, in the DASH study, despite a high-sodium intake, when the diet was rich in fruits and vegetables (and therefore dietary potassium), a lower BP was seen, despite a higher sodium intake [11]. Likewise, a meta-analysis pointed out the benefits of potassium intake in lowering BP but pointed out the great heterogeneity between studies [27]. In fact, some studies point out that it is the Na/K ratio in the urine that associates with increased risk for cardiovascular events [28]. Although it has been suggested that restriction in sodium intake that is accompanied by increased intake of potassium can profoundly improve the prevalence of hypertension and cardiovascular disease [29], the safety and efficacy of this recommendation among patients with CKD will need prospective trials.

Conclusions

Resistant hypertension is seen among 15% of the treated hypertensives. Risk factors for resistant hypertension include older age, CKD, obesity and diabetes mellitus. The four broad causes of resistant hypertension can be remembered with the mnemonic ABCD (adherence, biological–behavioral, CKD-secondary, drugs). However, before labeling the diagnosis of resistant hypertension, it is important to exclude pseudo-resistant hypertension using home BP monitoring in most patients and ambulatory BP monitoring in a few. Before thinking about the next antihypertensive drug, it is important to consider dietary sodium restriction. Educating the patient on how to interpret the food label and providing feedback by assessing sodium intake with 24 h urine collection are effective ways to implement sodium restriction. Sodium restriction can lower BP and among patients with proteinuria can even enhance the antiproteinuric effects of drugs that block the renin–angiotensin system. Accordingly, dietary sodium restriction is a potent—but forgotten—antihypertensive agent.

Conflict of interest statement

R.A. serves on the speakers' bureau of Merck and has served as a consultant for Dachii Sankyo and Takeda. All these companies manufacture and marked medications to treat hypertension.

Acknowledgements

This study was funded by NIH 2R01-DK062030-08.

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