1 Nature Reviews Cardiology 2013 Vol: 10(5):293-296. DOI: 10.1038/nrcardio.2013.23

How can resistant hypertension be identified and prevented?

Resistant hypertension is highly prevalent, and is the form of arterial hypertension that is most difficult to treat. Many patients diagnosed with this disease do not have resistant hypertension, but rather have mismanaged primary hypertension. In many cases blood pressure can be controlled by directly addressing underlying causes such as primary aldosteronism, obstructive sleep apnoea, or excessive neurogenic stimulation. Clinicians should ensure that appropriate blood-pressure measurements are used to diagnose resistant hypertension, explore a variety of drug combinations, and battle clinical inertia. Patients should comply with medication schedules and dietary modifications. Correction of these factors will greatly diminish the prevalence of 'resistant' hypertension and avoid the consequences of a persistently elevated blood pressure in these patients.

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Figures
Figure 1: The relationship between OSA and hypertension.These two conditions share common risk factors and pathogenic mechanisms. High salt intake could be particularly relevant to both conditions, through its effects on aldosterone secretion. Abbreviations: OSA, obstructive sleep apnoea; RAAS, renin–angiotensin–aldosterone system.
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References
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    • . . . Adequate control of blood pressure in patients with hypertension decreases the incidence of cardiovascular and cerebrovascular events.1 However, many patients are unresponsive to standard antihypertensive care . . .
    • . . . A diuretic agent must be considered for every patient with hypertension who requires three or more drugs for BP control.1, 2, 17 Spironolactone has been shown to be particularly effective in controlling 'resistant' hypertension, probably because patients with this condition frequently have primary hyperaldosteronism (discussed below).18 By controlling aldosterone levels, spironolactone induces rapid reversal of left ventricular hypertrophy and intracardiac volume overload.19 The ASPIRANT trial,20 in which patients with resistant hypertension were specifically examined, documented a significant reduction in systolic BP among patients treated with spironolactone . . .
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    • . . . Resistant hypertension is a clinical problem faced by both primary-care clinicians and specialists, and is defined as a blood pressure (BP) that remains above the target despite the concurrent use of three or more antihypertensive agents of different classes, including one diuretic.2 Large blood volume, related to excessive dietary salt ingestion, frequently characterizes the absence of response to standard therapy.2 The prevalence of resistant hypertension is unknown, but seems to be increasing over time3 and is lower among patients being treated in general medical practice than in those being cared for at specialized clinics.4 Data from the Spanish Ambulatory Blood Pressure Monitoring (ABPM) Registry suggest that 12% of patients with hypertension who are treated and followed up in the primary-care setting have a resistant hypertension.5 Instead of genuinely resistant hypertension, about one-third of these patients are likely to have 'white coat' hypertension, where patients exhibit elevated BP only in a clinical setting . . .
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    • . . . Resistant hypertension is a clinical problem faced by both primary-care clinicians and specialists, and is defined as a blood pressure (BP) that remains above the target despite the concurrent use of three or more antihypertensive agents of different classes, including one diuretic.2 Large blood volume, related to excessive dietary salt ingestion, frequently characterizes the absence of response to standard therapy.2 The prevalence of resistant hypertension is unknown, but seems to be increasing over time3 and is lower among patients being treated in general medical practice than in those being cared for at specialized clinics.4 Data from the Spanish Ambulatory Blood Pressure Monitoring (ABPM) Registry suggest that 12% of patients with hypertension who are treated and followed up in the primary-care setting have a resistant hypertension.5 Instead of genuinely resistant hypertension, about one-third of these patients are likely to have 'white coat' hypertension, where patients exhibit elevated BP only in a clinical setting . . .
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    • . . . Resistant hypertension, especially for prolonged periods, is accompanied by a substantial increase in the overall risk of cardiovascular and renal events, owing to the common coexistence of other risk factors such as obesity (particularly abdominal obesity), left ventricular hypertrophy, reduced estimated glomerular filtration rate, and microalbuminuria.6 Although resistant hypertension is an extreme phenotype,2 few genetic tests are available . . .
    • . . . 'White coat' hypertension is prevalent among patients diagnosed as having 'resistant' hypertension.2 Data from the Spanish ABPM Registry show that more than one-third of patients diagnosed with resistant hypertension have 'normal' ambulatory BP.5 In addition, up to 31% of patients taking three or more antihypertensive drugs who seem to have well-controlled BP when assessed in a clinical setting have at least one systolic or diastolic BP measurement >130 mmHg or >80 mmHg, respectively, in a 24 h period on ABPM.6 This phenomenon is known as 'masked' hypertension . . .
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    • . . . In an interesting retrospective study of >8,000 patients with hypertension and diabetes mellitus, Turchin et al. found an inverse relationship between the duration of time since the most-recent board certification of the patient's physician and the frequency of antihypertensive treatment intensification (an important measure of quality of care).8 Another retrospective cohort study in a Midwestern Veterans' Affairs administrative region has shown that intensification of treatment occurred in fewer than one-third of visits in which patients had elevated BP, regardless of whether the patient adherence to medication was good or poor.9 . . .
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    • . . . According to European10 and American11 guidelines, daily compliance and long-term adherence to therapy are the most-impotantobjectives in the treatment of patients with arterial hypertension . . .
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    • . . . According to European10 and American11 guidelines, daily compliance and long-term adherence to therapy are the most-impotantobjectives in the treatment of patients with arterial hypertension . . .
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    • . . . Such interactions help to determine patient adherence to treatment recommendations, self care, satisfaction, and health outcomes.12 A meta-analysis of patients with hypertension showed improved patient compliance after simplification of dosing regimens.13 This strategy can be achieved, especially in patients with several comorbidities, by selecting long-acting drugs or drug combinations to reduce the number of pills taken on a daily basis. . . .
  14. Basile, J. The importance of prompt blood pressure control. J. Clin. Hypertens. (Greenwich) 10 (Suppl. 1), 13-19 (2008) , .
    • . . . Pharmacological treatment of arterial hypertension is usually initiated with a combination of two antihypertensive drugs in an attempt to control BP within the first 3 months of therapy.14, 15 Nevertheless, resistant hypertension develops in 2% of patients receiving such treatment.16 Early identification of these individuals makes controlling their condition easier . . .
  15. Berlowitz, D. R. & Franklin, S. The clock is ticking: the case for achieving more rapid control of hypertension. J. Clin. Hypertens. (Greenwich) 12, 323-327 (2010) , .
    • . . . Pharmacological treatment of arterial hypertension is usually initiated with a combination of two antihypertensive drugs in an attempt to control BP within the first 3 months of therapy.14, 15 Nevertheless, resistant hypertension develops in 2% of patients receiving such treatment.16 Early identification of these individuals makes controlling their condition easier . . .
  16. Daugherty, S. L. et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation 125, 1635-1642 (2012) , .
    • . . . Pharmacological treatment of arterial hypertension is usually initiated with a combination of two antihypertensive drugs in an attempt to control BP within the first 3 months of therapy.14, 15 Nevertheless, resistant hypertension develops in 2% of patients receiving such treatment.16 Early identification of these individuals makes controlling their condition easier . . .
  17. Bobrie, G. et al. Sequential nephron blockade versus sequential renin-angiotensin system blockade in resistant hypertension: a prospective, randomized, open blinded endpoint study. J. Hypertens. 30, 1656-1664 (2012) , .
    • . . . A diuretic agent must be considered for every patient with hypertension who requires three or more drugs for BP control.1, 2, 17 Spironolactone has been shown to be particularly effective in controlling 'resistant' hypertension, probably because patients with this condition frequently have primary hyperaldosteronism (discussed below).18 By controlling aldosterone levels, spironolactone induces rapid reversal of left ventricular hypertrophy and intracardiac volume overload.19 The ASPIRANT trial,20 in which patients with resistant hypertension were specifically examined, documented a significant reduction in systolic BP among patients treated with spironolactone . . .
  18. Acelajado, M. C. & Calhoun, D. A. Aldosteronism and resistant hypertension. Int. J. Hypertens. Link , .
    • . . . A diuretic agent must be considered for every patient with hypertension who requires three or more drugs for BP control.1, 2, 17 Spironolactone has been shown to be particularly effective in controlling 'resistant' hypertension, probably because patients with this condition frequently have primary hyperaldosteronism (discussed below).18 By controlling aldosterone levels, spironolactone induces rapid reversal of left ventricular hypertrophy and intracardiac volume overload.19 The ASPIRANT trial,20 in which patients with resistant hypertension were specifically examined, documented a significant reduction in systolic BP among patients treated with spironolactone . . .
  19. Gaddam, K. et al. Rapid reversal of left ventricular hypertrophy and intracardiac volume overload in patients with resistant hypertension and hyperaldosteronism: a prospective clinical study. Hypertension. 55, 1137-1142 (2010) , .
    • . . . A diuretic agent must be considered for every patient with hypertension who requires three or more drugs for BP control.1, 2, 17 Spironolactone has been shown to be particularly effective in controlling 'resistant' hypertension, probably because patients with this condition frequently have primary hyperaldosteronism (discussed below).18 By controlling aldosterone levels, spironolactone induces rapid reversal of left ventricular hypertrophy and intracardiac volume overload.19 The ASPIRANT trial,20 in which patients with resistant hypertension were specifically examined, documented a significant reduction in systolic BP among patients treated with spironolactone . . .
  20. Václavík, J. et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension 57, 1069-1075 (2011) , .
    • . . . A diuretic agent must be considered for every patient with hypertension who requires three or more drugs for BP control.1, 2, 17 Spironolactone has been shown to be particularly effective in controlling 'resistant' hypertension, probably because patients with this condition frequently have primary hyperaldosteronism (discussed below).18 By controlling aldosterone levels, spironolactone induces rapid reversal of left ventricular hypertrophy and intracardiac volume overload.19 The ASPIRANT trial,20 in which patients with resistant hypertension were specifically examined, documented a significant reduction in systolic BP among patients treated with spironolactone . . .
  21. Calhoun, D. A. & White, W. B. Effectiveness of the selective aldosterone antagonist eplerenone in treating resistant hypertension. J. Am. Soc. Hypertens. 2, 462-468 (2008) , .
    • . . . For patients who cannot tolerate spironolactone, eplerenone also increases the potassium concentration in a dose-dependent manner (albeit with lower efficacy).21 Spironolactone is more frequently associated with adverse sexual effects: eplerenone shows a lower affinity for progesterone, androgen, and glucocorticoid receptors than spironolactone . . .
  22. Gashti, C. N. & Bakris, G. L. The role of calcium antagonists in chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 13, 155-161 (2004) , .
  23. Whelton, P. K. et al. Sodium, blood pressure, and cardiovascular disease: further evidence supporting the American Heart Association sodium reduction recommendations. Circulation 126, 2880-2889 (2012) , .
    • . . . Although the impact of a low-sodium diet on cardiovascular morbidity and mortality has been debated, many studies on which calls for the abandonment of low-sodium diet recommendations were based have now been shown to be flawed.23 Systolic and diastolic BP reductions of approximately 5.0 mmHg and 2.7 mmHg, respectively, can be obtained by simply reducing dietary sodium intake by 1.8 g.24 This approach also reduces the incidence of coronary heart disease, stroke, myocardial infarction, and all-cause mortality.25 A randomized trial, in which the effect of salt intake in patients with resistant hypertension was examined, showed a reduction in mean office systolic and diastolic BP of 22.7 mmHg and 9.1 mmHg, respectively, in patients following a low-salt diet.26 Patients should be educated on how to read food labels, and restaurants should provide information about the sodium content of their food . . .
  24. He, F. J. & MacGregor, G. A. Effect of modest salt reduction on blood pressure: a meta-analysis of randomized trials. Implications for public health. J. Hum. Hypertens. 16, 761-770 (2002) , .
    • . . . Although the impact of a low-sodium diet on cardiovascular morbidity and mortality has been debated, many studies on which calls for the abandonment of low-sodium diet recommendations were based have now been shown to be flawed.23 Systolic and diastolic BP reductions of approximately 5.0 mmHg and 2.7 mmHg, respectively, can be obtained by simply reducing dietary sodium intake by 1.8 g.24 This approach also reduces the incidence of coronary heart disease, stroke, myocardial infarction, and all-cause mortality.25 A randomized trial, in which the effect of salt intake in patients with resistant hypertension was examined, showed a reduction in mean office systolic and diastolic BP of 22.7 mmHg and 9.1 mmHg, respectively, in patients following a low-salt diet.26 Patients should be educated on how to read food labels, and restaurants should provide information about the sodium content of their food . . .
  25. Appel, L. J. et al. The importance of population-wide sodium reduction as a means to prevent cardiovascular disease and stroke: a call to action from the American Heart Association. Circulation 123, 1138-1143 (2011) , .
    • . . . Although the impact of a low-sodium diet on cardiovascular morbidity and mortality has been debated, many studies on which calls for the abandonment of low-sodium diet recommendations were based have now been shown to be flawed.23 Systolic and diastolic BP reductions of approximately 5.0 mmHg and 2.7 mmHg, respectively, can be obtained by simply reducing dietary sodium intake by 1.8 g.24 This approach also reduces the incidence of coronary heart disease, stroke, myocardial infarction, and all-cause mortality.25 A randomized trial, in which the effect of salt intake in patients with resistant hypertension was examined, showed a reduction in mean office systolic and diastolic BP of 22.7 mmHg and 9.1 mmHg, respectively, in patients following a low-salt diet.26 Patients should be educated on how to read food labels, and restaurants should provide information about the sodium content of their food . . .
  26. Pimenta, E. et al. Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension: results from a randomized trial. Hypertension 54, 475-481 (2009) , .
    • . . . Although the impact of a low-sodium diet on cardiovascular morbidity and mortality has been debated, many studies on which calls for the abandonment of low-sodium diet recommendations were based have now been shown to be flawed.23 Systolic and diastolic BP reductions of approximately 5.0 mmHg and 2.7 mmHg, respectively, can be obtained by simply reducing dietary sodium intake by 1.8 g.24 This approach also reduces the incidence of coronary heart disease, stroke, myocardial infarction, and all-cause mortality.25 A randomized trial, in which the effect of salt intake in patients with resistant hypertension was examined, showed a reduction in mean office systolic and diastolic BP of 22.7 mmHg and 9.1 mmHg, respectively, in patients following a low-salt diet.26 Patients should be educated on how to read food labels, and restaurants should provide information about the sodium content of their food . . .
  27. Sarafidis, P. A. Epidemiology of resistant hypertension. J. Clin. Hypertens. (Greenwich) 13, 523-528 (2011) , .
    • . . . Resistant hypertension is highly prevalent among patients with obesity or type 2 diabetes.27 High fasting plasma glucose was found to be an independent predictor of the development of resistant hypertension in the ASCOT28 population . . .
  28. Gupta, A. K. et al. Baseline predictors of resistant hypertension in the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT): a risk score to identify those at high-risk. J. Hypertens. 29, 2004-2013 (2011) , .
    • . . . Resistant hypertension is highly prevalent among patients with obesity or type 2 diabetes.27 High fasting plasma glucose was found to be an independent predictor of the development of resistant hypertension in the ASCOT28 population . . .
  29. Yoshita, K. et al. Relationship of alcohol consumption to 7-year blood pressure change in Japanese men. J. Hypertens. 23, 1485-1490 (2005) , .
    • . . . High alcohol intake (>2 units per day) is also related to a progressive increase in BP.29 Racial differences in sensitivity to the effects of alcohol between Asian and white populations should be considered, owing to a delayed oxidation of acetaldehyde by atypical aldehyde dehydrogenase in Asians.30 In future studies, the effects of a low-sodium diet should be tested in patients with resistant hypertension, severe obstructive sleep apnoea (OSA), and hyperaldosteronism.31 OSA and arterial hypertension share common risk factors and mechanisms, and excess salt intake can deteriorate both clinical conditions (Figure 1). . . .
  30. Li, D., Zhao, H. & Gelernter, J. Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians. Hum. Genet. 131, 725-737 (2012) , .
    • . . . High alcohol intake (>2 units per day) is also related to a progressive increase in BP.29 Racial differences in sensitivity to the effects of alcohol between Asian and white populations should be considered, owing to a delayed oxidation of acetaldehyde by atypical aldehyde dehydrogenase in Asians.30 In future studies, the effects of a low-sodium diet should be tested in patients with resistant hypertension, severe obstructive sleep apnoea (OSA), and hyperaldosteronism.31 OSA and arterial hypertension share common risk factors and mechanisms, and excess salt intake can deteriorate both clinical conditions (Figure 1). . . .
  31. Pimenta, E. et al. Increased dietary sodium is related to severity of obstructive sleep apnea in patients with resistant hypertension and hyperaldosteronism. Chest Link , .
    • . . . High alcohol intake (>2 units per day) is also related to a progressive increase in BP.29 Racial differences in sensitivity to the effects of alcohol between Asian and white populations should be considered, owing to a delayed oxidation of acetaldehyde by atypical aldehyde dehydrogenase in Asians.30 In future studies, the effects of a low-sodium diet should be tested in patients with resistant hypertension, severe obstructive sleep apnoea (OSA), and hyperaldosteronism.31 OSA and arterial hypertension share common risk factors and mechanisms, and excess salt intake can deteriorate both clinical conditions (Figure 1). . . .
  32. Clark, D., Ahmed, M. I. & Calhoun, D. A. Resistant hypertension and aldosterone: an update. Can. J. Cardiol. 28, 318-325 (2012) , .
    • . . . Primary aldosteronism occurs in 14–21% of patients with hypertension,32 and the symptoms are not specific, making diagnosis difficult . . .
  33. Mulatero, P. et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J. Clin. Endocrinol. Metab. 89, 1045-1050 (2004) , .
    • . . . However, approximately one-third to two-thirds of patients with primary aldosteronism are normokalemic.33 Patients frequently report fatigue, muscle weakness, cramps, headaches, and palpitations; polydipsia and polyuria can also coexist.34 In cases where primary aldosteronism is uncertain, the aldosterone:renin ratio should be quantified, bearing in mind that confounding effects can be produced by some antihypertensive drugs . . .
  34. Funder, J. et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 9, 3266-3281 (2008) , .
    • . . . However, approximately one-third to two-thirds of patients with primary aldosteronism are normokalemic.33 Patients frequently report fatigue, muscle weakness, cramps, headaches, and palpitations; polydipsia and polyuria can also coexist.34 In cases where primary aldosteronism is uncertain, the aldosterone:renin ratio should be quantified, bearing in mind that confounding effects can be produced by some antihypertensive drugs . . .
  35. Mulatero, P. et al. Drug effects on aldosterone/plasma renin activity in primary aldosteronism. Hypertension 40, 897-902 (2002) , .
  36. Pedrosa, R. P. et al. Obstructive sleep apnea. The most common secondary cause of hypertension associated with resistant hypertension. Hypertension 58, 811-817 (2011) , .
    • . . . OSA is common among patients with resistant hypertension,36 and this syndrome should be investigated in patients with poorly controlled hypertension who report snoring, witnessed apnoea, or frequent sleepiness during the day . . .
  37. Dudenbostel, T. & Calhoun, D. A. Resistant hypertension, obstructive sleep apnoea and aldosterone. J. Hum. Hypertens. 26, 281-287 (2012) , .
    • . . . Aldosterone misregulation might contribute to both high BP and OSA: an intriguing hypothesis is that excess aldosterone, which is common in patients with OSA, might promote accumulation of fluid within the neck, thus increasing upper airway resistance.37 Therapy with continuous positive airway pressure has been shown to moderately lower BP values in small, short-term, randomized trials.38 Resistant hypertension and OSA share common risk factors . . .
  38. Lozano, L. et al. Continuous positive airway pressure treatment in sleep apnea patients with resistant hypertension: a randomized, controlled trial. J. Hypertens. 10, 2161-2168 (2010) , .
    • . . . Aldosterone misregulation might contribute to both high BP and OSA: an intriguing hypothesis is that excess aldosterone, which is common in patients with OSA, might promote accumulation of fluid within the neck, thus increasing upper airway resistance.37 Therapy with continuous positive airway pressure has been shown to moderately lower BP values in small, short-term, randomized trials.38 Resistant hypertension and OSA share common risk factors . . .
  39. Kohler, M. & Stradling, J. R. Mechanisms of vascular damage in obstructive sleep apnea. Nat. Rev. Cardiol. 7, 677-685 (2010) , .
  40. Parati, G. & Esler, M. The human sympathetic nervous system: its relevance in hypertension and heart failure. Eur. Heart J. 33, 1058-1066 (2012) , .
    • . . . Ample evidence exists for the involvement of sympathetic nervous system activity in the development of primary hypertension.40 Reduced sensory neuron activity from the kidney to the central nervous system reduces the sympathetic activity to the heart, kidneys, and resistance vessels . . .
  41. Ruilope, L. M. & Schmieder, R. Current status of renal denervation in resistant hypertension. J. Am. Soc. Hypertens. 6, 414-416 (2012) , .
    • . . . The positive effects of renal sympathetic denervation on BP control in patients with hypertension uncontrolled with three or more drugs affirms the increased activity of the sympathetic nervous system as the main cause of resistance to medication.41 However, the effectiveness of drugs that block the sympathetic nervous system on BP control in patients unresponsive to antihypertensive therapy has not been examined. . . .
  42. Persell, S. D. Prevalence of resistant hypertension in the United States, 2003-2008. Hypertension 57, 1076-1080 (2011) , .
    • . . . Some of these parameters, such as race, age, and sex, are immutable.42 Clinicians and patients need to work together to improve BP control . . .
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