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HYPERTENSION

Resistant hypertension
Robert H Fagard
< Additional references are

published online only. To view these references please visit the journal online (http://heart.bmj. com/content/98/3.toc). Correspondence to Professor Robert H Fagard, University of Leuven KU Leuven, Hypertension Unit, UZ Gasthuisberg, Herestraat 49 B-3000 Leuven, Belgium; robert.fagard@uzleuven.be

High blood pressure is one of the leading risk factors inuencing the global burden of cardiovascular disease, resulting in increased incidence of all-cause and cardiovascular mortality, sudden death, stroke, coronary heart disease, heart failure, atrial brillation, peripheral artery disease, and renal insufciency. Hypertension affects about 25% of adults around the world and is estimated to lead to over seven million deaths each yeardthat is, about 13% of the total number of deaths worldwide. Lifestyle changes are able to lower blood pressure and prevent the development of hypertension, and antihypertensive drug treatment has been shown to reduce blood pressure and cardiovascular complications in hypertensive patients. Despite current knowledge on the management of hypertension and the availability of numerous effective antihypertensive drugs and combinations of drugs, hypertension remains inadequately controlled in many patients and a number of them are considered to have so-called resistant hypertension. The following issues will be discussed in this article on resistant hypertension: denition; prevalence; causes; target organ damage and cardiovascular complications; patient evaluation; and management. It is of note, however, that much of the knowledge on resistant hypertension is observational in nature, and that hard evidence is scarce, apart from a number of recent randomised controlled trials. This article will highlight new developments, with due respect for current generally accepted knowledge.

Denition
< Resistant hypertension is dened as the failure

to achieve goal blood pressure in patients who are on optimal doses of three or more antihypertensive agents from different classes, ideally one of which is a diuretic. < As dened, resistant hypertension includes patients whose blood pressure is controlled with the use of more than three medications.

condition, the high risk of having reversible causes of hypertension, and because they may benet from special diagnostic and therapeutic measures. Resistant hypertension should not be confounded with uncontrolled hypertension, which involves patients who are not at goal with fewer than three drugs, or with an inadequate treatment regimen. Finally, it is of note that the lack of blood pressure control is most often due to persistence of elevated systolic blood pressure, particularly at higher age when isolated systolic hypertension is prevalent.

PREVALENCE
The true prevalence of resistant hypertension remains unknown because of the absence of a specically designed large prospective study with forced titration. The prevalence has mainly been derived from clinical trials and has been estimated to range from 10% to almost 30% of general hypertensive patients in different studies. However, these estimates are certain to be inaccurate because of specic inclusion and exclusion criteria, and restricted treatment regimens in the various trials. In a recent community based observational study the prevalence of resistant hypertension was relatively modest. Persell4 used data collected from 2003 through 2008 in the National Health and Nutrition Examination Survey (NHANES), which uses standardised assessments of blood pressure and of prescription medications. Non-institutionalised non-pregnant adults with hypertension were classied as resistant if their blood pressure was $140 mm Hg (systolic) or $90 mm Hg (diastolic), and if they reported using antihypertensive medications from three different classes or drugs from $4 antihypertensive drug classes in the past month, regardless of blood pressure. These criteria for resistant hypertension were met by 8.9% of all US adults with hypertension and by 12.8% of the antihypertensive drug treated population. It is of note that 30% of these patients were controlled
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DEFINITION
Although the wording varies in different publications, resistant hypertension is conventionally dened as the failure to lower systolic and diastolic (ofce) blood pressure to goal in patients who are adhering to lifestyle measures and to the optimal doses of an appropriate regimen of three antihypertensive drugs from different classes, one of which is a diuretic.1e3 The goal blood pressure is usually dened as <140 mm Hg for systolic blood pressure and <90 mm Hg for diastolic blood pressure; in some studies the goal is lowered to <130/ 80 mm Hg for patients with diabetes mellitus or renal dysfunction, or even for all high and very high risk patients. Sometimes the diuretic is not an absolute requirement. It should be recognised that the denition is in fact arbitrary and imprecise, and, if taken literally, includes patients whose blood pressure is controlled with the use of four or more medications.3 Whereas these patients may not be truly resistant to therapy, they deserve special attention because of the seriousness of the
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Prevalence
< The true prevalence of resistant hypertension is

Causes
< It is important to distinguish between apparent

not known. < Post hoc analyses of clinical trials suggest a prevalence of 10% to almost 30% of general hypertensive patients. < According to the NHANES 2003e2008 survey, criteria for resistant hypertension are met by 8.9% of all US adults with hypertension and by 12.8% of the antihypertensive drug treated population.

and true resistant hypertension.

< Apparent resistant hypertension includes non-

adherence to treatment, cuff related artefacts, and white coat resistant hypertension. < Contributory factors and causes of true resistant hypertension involve: secondary causes of hypertension; obstructive sleep apnoea; volume overload; drug induced hypertension; obesity and excessive alcohol intake.

on $4 medications. The study also identied some characteristics of patients with resistant hypertension. Compared to those with controlled hypertension using one to three medication classes, adults with resistant hypertension were more likely to be older, obese and black, and to have reduced renal function, albuminuria and self reported diabetes mellitus, coronary heart disease, heart failure and stroke. The authors concluded that, although not rare, resistant hypertension is currently found in only a modest proportion of the general hypertensive population. However, if the possible contributions of poor adherence to treatment and of the white coat effect are taken into account, the true prevalence may even be less than the observed prevalence of 8.9% in the general hypertensive population. On the other hand, a number of patients with uncontrolled hypertension on one or two antihypertensive medications would probably not be controlled on $3 medications and might have been labelled as having resistant hypertension if their medications had been properly titrated to $3 drugs.

inadequate blood pressure control. The dosing schedule may be inconvenient, chaotic and not optimal, and may not include a diuretic or the most appropriate diuretic. Finally, the patient should be allowed to sit quietly for 5 min before blood pressure is measured.

Cuff related artefacts

The physician should be aware of cuff related artefacts. The cuff should be large enough so that the air bladder encircles at least 80% of the upper arm circumference and extends at least two thirds of its length. Blood pressure is overestimated when the cuff is too small for the arm. A rare cause of cuff related artefact is so-called pseudo-hypertension due to non-compressibility of severely arteriosclerotic or calcied brachial and radial arteries.

White coat resistant hypertension

Approximately 20e25% of patients with persistent ofce blood pressures $140/90 mm Hg have normal blood pressure on home blood pressure measurement or ambulatory monitoring, usually dened as awake blood pressure <135/85 mm Hg. Similarly, patients with resistant hypertension in the ofce may have normal out-of-ofce blood pressure. About a decade ago, Brown and colleagues5 reported that 28% of 118 patients with resistant hypertension, taking at least three antihypertensive drugs in combination, had normal awake ambulatory blood pressure as dened above. In the Spanish Ambulatory Blood Pressure Monitoring Registry,6 12.2% of 68 045 treated patients had resistant hypertension, dened as ofce blood pressure $140 mm Hg and/or 90 mm Hg while being treated with $3 antihypertensive drugs, one of them being a diuretic. After ambulatory blood pressure monitoring, 62.5% of them were classied as having true resistant hypertension and the remaining 37.5% as having white coat resistance. A signicant white coat effect should be suspected in patients who show signs of over treatment, such as orthostatic hypotension, and in patients with chronically high ofce blood pressure without target organ damage.

CAUSES
Resistant hypertension can be arbitrarily divided into two broad categories: true resistance, and apparent, spurious or false resistance. The prevalence of apparent resistance appears to be considerably higher than that of true resistance.

Apparent resistant hypertension Non-adherence to treatment

An important cause of apparent resistance is patient non-adherence to recommended lifestyle measures and/or drug treatment. A substantial number of patients discontinue their antihypertensive treatment, which may be due to a number of reasons, such as side effects and cost of medications, lack of consistent and continuous primary care, lack of strong physician motivation, poor understanding of instructions, and social and cultural barriers. Also the physician may be nonadherent and fail to follow guidelines for the management of hypertension. Surveys have indeed shown that physicians often fail to increase the number of drugs or the doses of drugs despite
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True resistant hypertension

A number of causes of true resistant hypertension are listed in box 1. Resistant hypertension may be
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renal function and albuminuria. The prevalence of the self reported medical histories of coronary heart disease, heart failure, and stroke amounted to, respectively, 22%, 10%, and 10% in resistant hypertension, and to 9.4%, 4.1%, and 3.8% in controlled hypertension (p<0.001 for all comparisons). It should be noted that the age difference was not taken into account in these univariable analyses, whereas age averaged, respectively, 66.4 and 59.5 years in resistant and controlled hypertension. In the Spanish study,6 patients with true resistant hypertension were compared to those with white coat resistant hypertension. Patients with true resistant hypertension were younger, comprised more men, had a worse risk prole with greater prevalence of diabetes and smoking, more organ damage, such as left ventricular hypertrophy, reduced renal function and microalbuminuria, and more cardiovascular complications. In a prospective follow-up study, Salles and colleagues9 investigated the importance of ambulatory blood pressure as a predictor of cardiovascular morbidity and mortality in 556 patients with resistant hypertension, representing 17% of patients in the outpatient clinic. Whereas ofce blood pressure showed no independent prognostic value, daytime and night-time systolic and diastolic blood pressure predicted a composite of fatal and non-fatal cardiovascular events after full adjustment, including ofce blood pressure, traditional risk factors, and cardiovascular diseases at baseline. The diagnosis of true resistant hypertension was also an independent predictor of the composite end point and all cause mortality, with a fully adjusted hazard ratio of about 2 in comparison with white coat resistant hypertension, and night-time blood pressures were better predictors than daytime blood pressures, as also observed in the general hypertensive population.10 11

Box 1 Causes of true resistant hypertension

< Secondary causes of hypertension, such as:

< <

<

<

renal artery stenosis renal parenchymal disease pheochromocytoma primary aldosteronism Obstructive sleep apnoea syndrome (OSAS) Volume overload progressive renal insufciency high sodium intake inadequate diuretic therapy Drug induced hypertension non-steroidal anti-inammatory drugs (NSAIDs) cocaine, amphetamines, other illicit drugs sympathomimetic agents oral contraceptive hormones ciclosporin, tacrolimus erythropoietin corticosteroids liquorice herbal compounds (ephedra, ma huang) Associated lifestyle conditions weight gain, obesity excessive alcohol intake

due to an unsuspected, specic, potentially curable secondary cause of hypertension, such as renal artery stenosis and pheochromocytoma. Recent studies have indicated that primary aldosteronism is more common in hypertension than generally accepted and prevalence rates of about 20% have been reported in resistant hypertension.7 Obstructive sleep apnoea has been identied in 83% of 41 consecutive patients with treatment resistant hypertension, and was both more common and more severe in men than in women.8 These patients are usually obese, short necked, and fall asleep at various time of the day. Volume overload is frequently associated with resistant hypertension, due to renal insufciency, inadequate diuretic therapy or high salt intake. Salt sensitive patients are particularly prone to the effects of excessive salt. Furthermore, a number of illicit drugs such as cocaine and amphetamines, and other substances such as non-steroidal anti-inammatory agents, pressor agents, and some non-traditional remedies may directly raise blood pressure or blunt the blood pressure lowering effect of antihypertensive medications, or both. Finally, resistant hypertension may be associated with obesity and heavy alcohol intake. Whether or not genetic factors play a role in resistance to treatment is currently under investigation.

PATIENT EVALUATION
A rst step in the evaluation of the patient with resistant hypertension is to conrm true resistance to treatment by use of the correct blood pressure measurement technique, and exclude apparent resistance, such as white coat resistant hypertension, by home or ambulatory blood pressure monitoring, and accurate assessment of treatment adherence. Next, contributing lifestyle factors should be identied and reversed, and interfering substances should be discontinued or minimised. Target organ damagedsuch as left ventricular hypertrophy, retinopathy, and renal insufciencyd and clinical cardiovascular complications need to be documented and patients should be screened for secondary causes of resistant hypertension by medical history, physical examination, biochemical evaluation, and/or non-invasive imaging, with particular attention paid to a number of symptoms and signs as summarised in the algorithm in box 2. Biochemical evaluation of the patient with treatment resistant hypertension should routinely include a metabolic prole including sodium,
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TARGET ORGAN DAMAGE AND CLINICAL COMPLICATIONS

In the NHANES survey, patients with resistant hypertension were compared to patients with controlled hypertension using one to three medications.4 They were more likely to have reduced
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Box 2 Diagnostic and management algorithm in resistant hypertension

potassium, glucose, and creatinine; urinalysis; and plasma aldosterone and renin or renin activity. A 24 h urine collection is useful to estimate dietary sodium and potassium intake, calculate creatinine clearance, and measure aldosterone excretion. Urinary or plasma metanephrines/catecholamines are indicated when pheochromocytoma is suspected. Non-invasive imaging is reserved for patients in whom there is a suspicion of renal artery stenosis or adrenal adenoma or tumour.
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TREATMENT RECOMMENDATIONS
Treatment of patients with resistant hypertension includes appropriate lifestyle changes, discontinuation or minimisation of interfering substances, and use of effective multidrug regimens and device therapy. Although not specically evaluated in patients with resistant hypertension, lifestyle changes to lower blood pressure include weight loss in case of overweight or obesity; moderate intensity exercise for a minimum of 30 min on most days of
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the week; dietary salt reduction, ideally to <100 mEq of sodium/24 h; and moderation of alcohol intake to no more than two drinks per day for most men and one drink per day for women or lighter-weight persons. A high bre, low fat diet is also recommended. Specic treatment of secondary causes of hypertension and obstructive sleep apnoea is beyond the scope of the current review (box 2).

Pharmacological treatment
< The most rational triple drug regimen appears to

Drug therapy Diuretic therapy

Resistant hypertension is often at least partly related to lack of, or underuse of, diuretic therapy necessary to control occult inappropriate volume expansion. This condition would require adding a diuretic, increasing the dose, or changing the diuretic class. The long acting thiazide diuretic chlorthalidone should be preferentially used in patients with resistant hypertension because it has been shown to produce greater 24 h ambulatory blood pressure reduction than hydrochlorothiazide, with the largest difference occurring during the night.12 Loop diuretics are usually reserved for patients with chronic kidney disease, but may help to increase blood pressure control in other patients.

be a blocker of the renin angiotensin system, a calcium channel blocker, and an appropriate diuretic at effective doses. < According to properly designed recent studies in treatment resistant hypertension, the additional blood pressure lowering effects of the mineralocorticoid receptor antagonist spironolactone and of the endothelial receptor antagonist darusentan are modest. < Other drug classes can be included in the multiple drug regimen, depending on clinical circumstances.

Drug combinations
Most combinations of two antihypertensive drugs produce additive antihypertensive benet. In recent guidelines the following combinations are considered most suitable because of their pronounced blood pressure lowering effect, cardiovascular protection, and optimal tolerability: thiazide diuretic or calcium channel blocker with an ACE inhibitor or angiotensin receptor blocker. Although there are no hard scientic data, the combination of a thiazide diuretic, a calcium channel blocker, and a converting enzyme inhibitor or angiotensin receptor blocker, which act by complementary mechanisms, is probably the most rational triple drug regimen. Other drugs, such as b-blockers, a-blockers, centrally acting agents, or potent vasodilators such as hydralazine or minoxidil, may be included in the multiple drug approach depending on the clinical circumstances, though adverse effects may be common. The combined use of a b-blocker and a thiazide diuretic may potentiate the development of diabetes mellitus, particularly in the overweight or obese patient. The combination of a converting enzyme inhibitor and an angiotensin receptor blocker is not recommended because of the increased incidence of adverse effects and even some harm observed in the high risk patients of the ONTARGET trial. Two types of drugdthe mineralocorticoid receptor antagonist spironolactone and the endothelin receptor antagonist darusentandhave been evaluated as additional treatment in resistant hypertension and are discussed separately.

doses of spironolactone in the lowering of blood pressure in patients with resistant hypertension. For example, spironolactone 12.5e50 mg daily lowered blood pressure by an additional 25/ 12 mm Hg in 76 patients with poorly controlled hypertension.13 In the non-randomised post hoc analysis of the Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering arm, the addition of spironolactone to a triple drug treatment regimen led to a signicant decrease of 21.9/9.5 mm Hg. However, the results of a properly designed placebo controlled trial were more modest. Vaclavik and colleagues14 randomly assigned 117 patients with resistant hypertension, dened as ofce blood pressure >140/90 mm Hg despite treatment with at least three antihypertensive drugs including a diuretic, to receive 25 mg spironolactone or a placebo as add-on therapy to their antihypertensive medications. The primary end point was daytime ambulatory blood pressure. After 8 weeks, the difference in mean blood pressure fall was 5.4 mm Hg for systolic blood pressure (p0.02) and 1.0 mm Hg for diastolic blood pressure (p0.36) in favour of the spironolactone group. The difference amounted to 9.8 (p<0.01)/1.0 (p0.40) mm Hg for average 24 h blood pressure and to 6.5 (p0.01)/2.5 (p0.08) mm Hg for ofce blood pressure. With regard to predictors of the response to spironolactone, the authors observed that the reduction of systolic 24 h blood pressure was signicantly greater in patients with low plasma renin activity (p<0.01) or high aldosterone-to-renin ratio (p0.02), and tended to be better in those with low serum potassium (p0.07), but was not related to serum aldosterone (p0.61). The authors note that the appropriate dosing range for spironolactone has not been well dened in resistant hypertension, and that it is possible that a higher dose of the drug could have led to a greater blood pressure decrease.

Mineralocorticoid receptor antagonists

In the past decade a number of small uncontrolled trials have shown the benecial effect of small
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Endothelin receptor antagonists

Two recent randomised, double blind, placebo controlled trials15 16 assessed the potential role of
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the new vasodilatory, selective endothelin type A antagonist darusentan in, respectively, 379 and 849 patients with systolic blood pressure $140 mm Hg ($130 mm Hg in case of diabetes or chronic kidney disease) who were receiving at least three blood pressure lowering drugs, including a diuretic, at full or maximum tolerated doses. In the rst study15 patients were randomly assigned to 14 weeks treatment with placebo or darusentan 50 mg, 100 mg or 300 mg taken once daily. The mean reductions in ofce blood pressure were 9/ 5 mm Hg with placebo and 17/10, 18/10 and 18/ 11 mm Hg with the three doses of darusentan (p<0.001 for all effects). Oedema or uid retention occurred in 27% of the patients given darusentan compared with 14% given placebo; ve patients on darusentan had cardiac related serious adverse events. In the second trial,16 patients were randomised to darusentan, placebo or the central a2 agonist guanfacine. Decreases from baseline to week 14 in ofce blood pressure (the primary end point) for darusentan (15 mm Hg) were greater than for guanfacine (12 mm Hg, p<0.05) but not greater than for placebo (14 mm Hg). Darusentan, however, reduced mean 24 h systolic blood pressure (9 mm Hg) more than placebo (2 mm Hg) or guanfacine (4 mm Hg) (p<0.001 for each comparison). Fluid retention/oedema was present in 28% of the patients on darusentan versus 12% in each of the other groups. The overall results suggest that selective endothelial receptor antagonists may have a role in the treatment of resistant hypertension, but there is concern about volume retention and potential exacerbation of heart failure, and the long term benet is not known.

Device therapy: renal denervation

< Renal denervation involves a catheter based

approach using radiofrequency energy to selectively disrupt the renal nerves. < In a recent randomised trial, renal denervation resulted in a substantial decrease of ofce blood pressure, but the results were more modest for out-of-ofce blood pressure. < Current evidence indicates that the technique has a favourable safety prole.

Device therapy Renal denervation

Efferent sympathetic outow to the kidney stimulates renin release, increases tubular sodium reabsorption, and reduces renal blood ow; afferent signals from the kidney modulate central sympathetic outow and contribute to neurogenic hypertension.17 Based on the evidence of the role of renal sympathetic nerves in various aspects of blood pressure control, a catheter based approach using radiofrequency energy to selectively target and disrupt the renal nerves has been developed. Following observational safety and feasibility studies, the Symplicity HTN-2 Trial, a multicentre, prospective randomised trial,18 was performed in patients who had a baseline systolic blood pressure $160 mm Hg ($150 mm Hg for patients with type 2 diabetes) despite taking three or more antihypertensive drugs. Patients were taking a median of ve medications, and diuretics, including spironolactone, were used in more than 89% of them. Secondary hypertension and white coat hypertension were not dened as exclusion criteria. One hundred and six patients were randomised to undergo renal denervation with previous treatment (n52) or to maintain previous treatment (n54); the control group did not undergo a sham procedure,
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which would have provided double blinding. After 6 months, ofce blood pressure was reduced by 32/ 12 mm Hg from the baseline value of 178/ 96 mm Hg (p<0.001) in the renal denervation group, whereas blood pressure in the control group changed by 1/0 mm Hg from 178/97 mm Hg at baseline (p>0.75). Between-group differences in blood pressure at 6 months amounted to 33/ 11 mm Hg (p<0.001). Systolic blood pressure was <140 mm Hg in 39% and 6% of the patients, respectively (p0.04). Results on home blood pressure and 24 h ambulatory blood pressure in smaller numbers of patients were roughly concordant, although less pronounced. For example, 24 h blood pressure recordings, available in 20 patients in the renal denervation group, showed a mean decrease of 11/7 mm Hg, whereas blood pressure did not change signicantly for the 25 patients in the control group (3/1 mm Hg). There were no serious procedure related or device related complications and occurrence of adverse events did not differ between groups. There were no adverse effects on the kidney, and this was also the case for patients with impaired renal function In summary, the available evidence indicates that catheter based renal denervation has a favourable safety prole and results in potentially substantial and sustained blood pressure reduction in patients with drug resistant hypertension. In pilot studies, no loss of antihypertensive response was evident with follow-up of 2 years. Effects on cardiovascular morbidity and mortality are currently unknown.

Carotid baroreex activation

Another device based therapy of resistant hypertension is carotid baroreex activation, in which stimulating electrodes are implanted in the perivascular space around the carotid sinuses. The Rheos Baroreex Hypertension Therapy System enhances afferent nerve trafc from the baroreceptors to the cardiovascular control centres of the brain, which subsequently reduce sympathetic outow and blood pressure. The Device Based Therapy in Hypertension Trial19 was a multicentre, prospective, non-randomised feasibility study. Its purpose was to assess the safety and efcacy of the Rheos system over 3 months in 45 patients with resistant hypertension, dened as blood pressure $160/90 mm Hg despite receiving at least
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unchanged after 3 months and increased signicantly after 12 months in 22 participants. There was no evidence of orthostatic hypotension. In a multicentre randomised study, presented at the 61st Annual Scientic Session of the American College of Cardiology in April 2011,20 the Rheos system was implanted in 265 patients with resistant hypertension $160/80 mm Hg. All patients, whose ofce blood pressure averaged 178/ 103 mm Hg, were implanted with the device, and then randomised in a 2:1 ratio to baroreex activation therapy for 12 months (group A) or control treatment for the rst 6 months, with the system switched off, followed by baroreex activation therapy for the following 6 months (group B). At the end of the 6 month double blind period, the percentage of patients with $10 mm Hg systolic blood pressure reduction was 54% in group A and 46% in group B (p0.97); the difference of 7.7% did not achieve the goal difference of >20%. Systolic blood pressure was 140 mm Hg or less in, respectively, 42% and 24% (p0.005) at 6 months. Of the 97 responders in group A after 6 months, 88% were considered sustained responders after 12 months. When groups A and B were combined, systolic blood pressure was 140 mm Hg or less in over 50% of the patients after 12 months. With regard to safety, the authors concluded that the end point of long term device safety was met whereas the end point of short term procedure related adverse events was not. Only 75% of patients were free of procedural adverse events at 30 days, but 76% of adverse events fully resolved. The authors concluded that the results justify further development and investigation of baroreex activation therapy.

Device therapy: carotid baroreex activation

< Stimulating electrodes are implanted in the

perivascular space around the carotid sinuses and reduce sympathetic outow from the cardiovascular control centres from the brain. < The blood pressure response was favourable in uncontrolled studies, but less convincing in a randomised controlled trial. < There is currently concern about the overall safety of the technique.

three antihypertensive agents including a diuretic; the median number of medications was ve. Medications were kept constant for 2 months before entry and during the rst 3 months of therapy, except when medically necessary. In the 37 evaluable patients after 3 months, the change in ofce blood pressure averaged 21/12 mm Hg from a baseline value of 179/105 mm Hg, and heart rate decreased by 8 beats/min (bpm) from 80 bpm at baseline. The reduction in 24 h systolic and diastolic blood pressure, and heart rate, monitored in 26 subjects, amounted to, respectively, 6 mm Hg (p0.10), 4 mm Hg (p0.04), and 5 bpm (p<0.001). Seventeen subjects completed 2 years of device therapy, at which time ofce blood pressure had decreased by 33/22 mm Hg (p<0.01) and 24 h blood pressure by 24/13 mm Hg (p<0.05). The non-randomised cohort of 10 eligible patients who had declined participation in the trial failed to show a signicant change in ofce blood pressure. With regard to safety, seven patients experienced a procedure related serious adverse event and one patient a device related serious adverse event. Serum creatinine remained

PERSPECTIVES
Because of some variability in the denition of treatment resistant hypertension in different studies, which limits their comparability to some extent, there is need for one and the same universal denition. The prevalence of resistant hypertension varies among studies but the true prevalence will probably remain unknown because a prospective study with forced and exible drug titration may never be performed in the general hypertensive population. The techniques to distinguish between apparent and true resistant hypertension are available and the causes of true resistance are well known, but more work is needed to determine whether or not genetic factors are involved. Apart from the management of specic causes of resistant hypertension, an armamentarium of antihypertensive drug classes and drugs are available for the treatment of primary resistant hypertension. Rational combinations of three complementary drug classes have been proposed, but have in fact never been tested in randomised controlled trials or outcome studies. The potential of higher doses of spironolactone and of newer more selective endothelin type A receptor antagonists as add-on therapy should be further explored. Because of the heterogeneous
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pathophysiology of hypertension, development of drugs which target new mechanisms are still welcome. Renal denervation and carotid baroreex activation therapy have recently been shown to decrease blood pressure on top of multiple drug therapy in resistant hypertension; however, there is still a need for a properly designed double blind trial for renal denervation therapy and the safety concern for carotid baroreex activation therapy should be resolved. Furthermore it would be of interest to know if the blood pressure lowering effects of the two types of device therapy are additive, which would be helpful in case of persistent resistance after application of one of them.
Competing interests In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conicts of interest that might cause a bias in the article. The author has no competing interests. Provenance and peer review Commissioned; internally peer reviewed.
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REFERENCES
1. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42:1206e52. Mancia G, De Backer G, Dominiczak A; Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105e87. Calhoun DA, Jones D, Textor S. Resistant hypertension: diagnosis, evaluation and treatment. A scientic statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008;51:1403e19. This scientic statement from the American Heart Association represents a comprehensive state of the art manuscript on resistant hypertension up to 2007e8. Persell SD. Prevalence of resistant hypertension in the United States, 2003-2008. Hypertension 2011;57:1076e80. This population based observational study is likely to provide the most reliable estimate of the prevalence of resistant hypertension to date. Brown MA, Buddle ML, Martin A. Is resistant hypertension really resistant? Am J Hypertens 2001;14:1263e9. De la Sierra A, Segura J, Banegas JR, et al. Clinical features of 8295 patients with resistant hypertension classied on the basis of ambulatory blood pressure monitoring. Hypertension 2011;57:898e902. In this large observational study ambulatory blood pressure monitoring revealed that 37.5% of the patients with resistant hypertension could be classied as having white coat resistance. Calhoun DA, Nishizaka MK, Zaman MA, et al. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension 2002;40:892e6.

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20.

7.

This study was one of the rst to emphasise the high prevalence of primary aldosteronism among patients with resistant hypertension. Logan AG, Perlikowski SM, Mente A, et al. High prevalence of unrecognized sleep apnea in drug-resistant hypertension. J Hypertens 2001;19:2271e7. This study identied obstructive sleep apnoea as a prevalent cause of resistant hypertension. Salles GF, Cardoso CRL, Muxfeldt ES. Prognostic inuence of ofce and ambulatory blood pressures in resistant hypertension. Arch Intern Med 2008;168:2340e6. This study found that ambulatory blood pressure was a better predictor of cardiovascular morbidity and mortality than ofce blood pressure and that night-time blood pressure was a better predictor than daytime blood pressure in resistant hypertension. Fagard RH, Cornelissen VA. Incidence of cardiovascular events in white-coat, masked and sustained hypertension versus true normotension: a meta-analysis. J Hypertens 2007;25:2193e8. Fagard RH, Celis H, Thijs L, et al. Daytime and night-time blood pressure as predictors of death and cause-specic cardiovascular events in hypertension. Hypertension 2008;51:55e61. Ernst ME, Carter BL, Goerdt CJ, et al. Comparative antihypertensive effect of hydrochlorothiazide and chlorthalidone on ambulatory and ofce blood pressure. Hypertension 2006;47:352e8. Nishizaka MK, Zaman MA, Calhoun DA. Efcacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens 2003;16:925e30. Vaclavik J, Sedlak R, Plachy M, et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT). A randomized, double-blind, placebo-controlled trial. Hypertension 2011;57:1069e75. Whereas uncontrolled studies observed large decreases of blood pressure with spironolactone, this rst randomised placebo controlled trial showed a more modest effect. Weber MA, Black H, Bakris G, et al. A selective endothelinreceptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomized, double-blind, placebo-controlled trial. Lancet 2009;374:1423e31. This study showed that the selective endothelin receptor antagonist darusentan has a modest additional blood pressure lowering effect in resistant hypertension, but that there is concern about volume retention. Bakris GL, Lindholm LH, Black HR, et al. Divergent results using clinic and ambulatory blood pressure. Report of a DarusentanResistant Hypertension Trial. Hypertension 2010;56:824e30. Schlaich MP, Krum H, Sobotka PA, et al. Renal denervation and hypertension. Am J Hypertens 2011;24:635e42. Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN-2 Trial): a randomized controlled trial. Lancet 2010;376:1903e9. Renal denervation produced a substantial reduction in ofce blood pressure in this randomised controlled though not double blind trial, but the result was less pronounced for ambulatory blood pressure. Scheffers IJM, Kroon AA, Schmidli J, et al. Novel baroreex activation therapy in resistant hypertension. J Am Coll Cardiol 2010;56:1254e8. This prospective non-randomised feasibility study showed that carotid baroreex activation decreases ofce and ambulatory blood pressure in patients with resistant hypertension, but raises safety concerns. Bisognano JD, Bakris G, Nadim MK, et al. Baroreex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebocontrolled Rheos Pivotal Trial. J Am Coll Cardiol 2011;58:765e73.

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