Resistant Hypertension

doi:10.1016/j.jacc.2008.08.036 2008;52;1749-1757 J. Am. Coll. Cardiol.

Pantelis A. Sarafidis, and George L. Bakris Resistant Hypertension: An Overview of Evaluation and Treatment

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Journal of the American College of Cardiology Vol. 52, No. 22, 2008© 2008 by the American College of Cardiology Foundation ISSN 0735-1097/08/$34.00P

STATE-OF-THE-ART PAPER

Resistant HypertensionAn Overview of Evaluation and Treatment

Pantelis A. Sarafidis, MD, PHD,* George L. Bakris, MD, FAHA, FASN†

Thessaloniki, Greece; and Chicago, Illinois

Resistant hypertension is defined as failure to achieve goal blood pressure (BP) when a patient adheres to themaximum tolerated doses of 3 antihypertensive drugs including a diuretic. Although the exact prevalence of re-sistant hypertension is currently unknown, indirect evidence from population studies and clinical trials suggeststhat it is a relatively common clinical problem. The prevalence of resistant hypertension is projected to increase,owing to the aging population and increasing trends in obesity, sleep apnea, and chronic kidney disease. Man-agement of resistant hypertension must begin with a careful evaluation of the patient to confirm the diagnosisand exclude factors associated with “pseudo-resistance,” such as improper BP measurement technique, thewhite-coat effect, and poor patient adherence to life-style and/or antihypertensive medications. Education andreinforcement of life-style issues that affect BP, such as sodium restriction, reduction of alcohol intake, andweight loss if obese, are critical in treating resistant hypertension. Exclusion of preparations that contribute totrue BP treatment resistance, such as nonsteroidal anti-inflammatory agents, cold preparations, and certainherbs, is also important. Lastly, BP control can only be achieved if an antihypertensive treatment regimen isused that focuses on the genesis of the hypertension. An example is volume overload, a common but unappreci-ated cause of treatment resistance. Use of the appropriate dose and type of diuretic provides a solution to over-come treatment resistance in this instance. (J Am Coll Cardiol 2008;52:1749–57) © 2008 by the AmericanCollege of Cardiology Foundation

ublished by Elsevier Inc. doi:10.1016/j.jacc.2008.08.036

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ypertension is the most common chronic disease ineveloped societies, affecting �25% of adults (1). Meta-nalyses have demonstrated a linear relationship betweenevel of blood pressure (BP) and risk for cardiovascularvents (2–4). Suboptimal BP control is, consequently, theost common attributable risk for death worldwide, being

esponsible for 62% of cerebrovascular disease and 49% ofschemic heart disease as well as an estimated 7.1 millioneaths a year (5).In the U.S., both the net and age-adjusted prevalence

atios of hypertension continue to increase. Recent datauggest, however, a slight improvement in hypertensionwareness, treatment, and control (6). The rates of hyper-ension treatment and control in Europe are much lowerhan in the U.S. (7). Several large hypertension outcomerials also demonstrate a failure to achieve BP goals in spitef protocol-defined treatment regimens. In these trials, 20%o 35% of participants could not achieve BP control despiteeceiving �3 antihypertensive medications (8–10) (Fig. 1).

rom the *Section of Nephrology and Hypertension, 1st Department of Medicine,HEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; and

he †Hypertensive Diseases Unit, Department of Medicine, Section of Endocrinol-gy, Diabetes, and Metabolism, University of Chicago Pritzker School of Medicine,hicago, Illinois.

cManuscript received June 20, 2008; revised manuscript received August 18, 2008,

ccepted August 26, 2008.

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This article provides the clinician with an overview of theatient characteristics associated with resistant hyperten-ion, the diagnostic evaluation to assess the problem, andhe treatment strategies for optimizing BP control.

efinition and Prevalencef Resistant Hypertension

he Joint National Committee 7 defines resistant hyper-ension as failure to achieve goal BP (�140/90 mm Hg forhe overall population and �130/80 mm Hg for those withiabetes mellitus or chronic kidney disease) when a patientdheres to maximum tolerated doses of 3 antihypertensiverugs including a diuretic (11). This definition does notpply to patients who have been recently diagnosed withypertension (12). Moreover, resistant hypertension is notynonymous with uncontrolled hypertension. The latterncludes all hypertensive patients who lack BP control underreatment, namely, those receiving an inadequate treatmentegimen, those with poor adherence, and those with unde-ected secondary hypertension, as well as those with truereatment resistance. By this definition, patients with resis-ant hypertension may achieve BP control with full doses of

or more antihypertensive medications (13,14). Althoughhe definition of resistant hypertension is arbitrary relativeo the number of antihypertensive medications required, the
oncept of resistant hypertension is focused on identifying
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1750 Sarafidis and Bakris JACC Vol. 52, No. 22, 2008Resistant Hypertension November 25, 2008:1749–57

patients who are at high risk ofhaving reversible causes of hyper-tension and/or patients who, be-cause of persistently high BP lev-els, may benefit from specialdiagnostic or therapeutic consid-erations (13).

The prevalence of resistant hy-pertension in the general popu-lation is unknown because of aninadequate sample size of pub-lished studies as well as the fea-sibility of doing a large enoughprospective study that would an-swer the question (15,16). Smallstudies, however, demonstrate aprevalence of resistant hyperten-sion that ranges from �5% ingeneral medical practice to

50% in nephrology clinics (15).Based on data from the National Health And Nutrition

xamination Survey, 2003 to 2004, 58% of people beingreated for hypertension achieve BP levels �140/90 mm Hg6); control rates among those with diabetes mellitus orhronic kidney disease are �40% (6,17). In Europe, theituation is worse, with control rates among treated hyper-ensive patients between 19% and 40% in 5 large countries7). Such data suggest that resistant hypertension is moreommon than appreciated; however, accurate estimates are

Abbreviationsand Acronyms

ACE � angiotensin-converting enzyme

ARB � angiotensin-receptor blocker

BP � blood pressure

CCB � calcium-channelblocker

eGFR � estimatedglomerular filtration rate

ERA � endothelin-receptorantagonist

NSAID � nonsteroidal anti-inflammatory drug

RAS � renin-angiotensinsystem

Figure 1 Percent of Patients Reaching JNC-7 BP Goals

Percent of patients reaching the Joint National Committee 7 (JNC-7) bloodpressure (BP) goals in the following trials: ACCOMPLISH (Avoiding Cardiovascu-lar Events Through Combination Therapy in Patients Living With Systolic Hyper-tension): amlodipine plus benazepril versus benazepril plus hydrochlorothiazide(56); INVEST (International Verapamil-Trandolapril Study): verapamil versusatenolol (10); CONVINCE (Controlled Onset Verapamil Investigation of Cardio-vascular End Points): verapamil versus atenolol (57); ALLHAT (Antihypertensiveand Lipid-Lowering Treatment to Prevent Heart Attack Trial): chlorthalidone ver-sus lisinopril versus amlodipine (8); and LIFE (Losartan Intervention For End-point Reduction in Hypertension Study): losartan versus atenolol (9). Note that,in all of these trials, more than two-thirds of the patients were receiving atleast 2 antihypertensive agents and about one-third were receiving 3 or moreantihypertensive agents.

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ot possible, as control rates under treatment are affected byany factors.

rognosis of Resistant Hypertension

here are no studies specifically powered to address therognosis of persons with resistant hypertension. However,s evident from all population studies on hypertension-elated target-organ damage, the risks of myocardial infarc-ion, stroke, heart failure, and renal failure directly relate tohe level of BP (3,11).

These observations coupled with the most commonomorbid conditions seen in patients with resistant hyper-ension, namely, obesity, diabetes, or chronic kidney disease,ranslate into an unfavorable prognosis if the BP goal is notchieved (13). The extent of cardiovascular morbidity andortality reduction with achievement of the BP goal has not

een evaluated; however, the benefits are evident by resultsf major outcome studies (2,11,18,19).

tiology of “Pseudo-Resistance”

he term “pseudo-resistance” refers to lack of BP controlith appropriate treatment in a patient who does not have

esistant hypertension. Several factors contribute to elevatedP readings and produce the perception of resistant hyper-

ension (12–16) (Table 1). Such factors include the follow-ng: 1) suboptimal BP measurement technique; 2) thehite-coat effect; and 3) poor adherence to prescribed

herapy and other causes described in the following text13,14). A careful evaluation to exclude these factors beforeabeling someone as having resistant hypertension should beerformed.Although guidelines to properly assess office BP are

idely available (20), several common mistakes often pro-uce falsely elevated BP readings. Such mistakes include notllowing the patient to sit quietly for adequate time, takingingle instead of triple readings, using cuffs that are toomall for the arm, recent smoking, and not fully supportinghe arm at heart level (12,13,16). In older patients, theresence of heavily calcified or arteriosclerotic arteries thatannot be fully compressed is common and results inverestimation of intra-arterial BP (12,16).The “white-coat effect,” defined as an elevation of BP

uring a clinic visit resulting in higher office readings thant home or ambulatory BP readings (21), is another cause ofseudo-resistance. The white-coat effect is common amongatients with perceived resistant hypertension; �25% ofuch patients referred for resistant hypertension achieve goalP under treatment when ambulatory measurements areerformed (22). Patients with apparent resistant hyperten-ion due to the white-coat effect have less target-organamage compared with truly resistant hypertensive patients23,24). Therefore, such patients should have home ormbulatory BP measurements (12).

Poor adherence to an adequate antihypertensive regimen
s another cause of apparent resistant hypertension. Studies


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1751JACC Vol. 52, No. 22, 2008 Sarafidis and BakrisNovember 25, 2008:1749–57 Resistant Hypertension

uggest that up to 40% of newly diagnosed hypertensiveatients will discontinue their antihypertensive medicationsuring the first year, with only 40% of the remainingatients continuing their therapy over the next decade25–27). An evaluation of 4,783 hypertensive patients en-olled in phase IV clinical studies, with follow-up rangingrom 30 to 330 days, demonstrated a discontinuation rate ofntihypertensive drug of �50% within 1 year (28). More-ver, there was an inverse relationship between the likeli-ood of early treatment discontinuation and the frequencyf the daily dosing regimen. Factors that improve medica-ion adherence include the following: 1) selection of agentsith low side effect profiles such as blockers of the renin-

ngiotensin system (RAS); 2) avoidance of complicatedosing schedules so that once-daily agents either alone or inxed dose would be preferred; 3) use of pill boxes or familyo help patients with memory deficits or psychiatric disor-ers; and 4) improved communication between the patientnd physician to ensure that the patient understands theegimen and why the medication should be taken in the wayrescribed. Failing to educate the patient about the impor-ance of achieving BP goals, the predicted side effects of thegents, and the cost of medication are the most commoneasons for drug discontinuation (29,30).

A relatively surprising cause of pseudo-resistant hyper-ension is suboptimal dosing of antihypertensive agents ornappropriate combinations of agents. Data from a clinicalypertension specialty clinic demonstrated that either in-reasing the dose or initiating or switching to the properiuretic was the most common change that achieved BPoal among patient referred for resistant hypertension (31).

An important culprit that contributes to the genesis ofseudo-resistant hypertension is clinical inertia, defined ashe conscious decision by a clinician to not adequately treatcondition despite knowing that it is present (32). Despite

fforts to translate evidence-based guidelines into clearecommendations for clinical practice (11), many physicians

auses of Pseudo-Resistant Hypertension

Table 1 Causes of Pseudo-Resistant Hypertension

Improper blood pressure measurement

Heavily calcified or arteriosclerotic arteries that are difficult to compress (inelderly persons)

White-coat effect

Poor patient adherence

Side effects of medication

Complicated dosing schedules

Poor relations between doctor and patient

Inadequate patient education

Memory or psychiatric problems

Costs of medication

Related to antihypertensive medication

Inadequate doses

Inappropriate combinations

Physician inertia (failure to change or increase dose regimens when not at goal)

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nertia may be due to lack of training and experience in theroper use of antihypertensive agents or an overestimationf care already provided (33). Several studies (34,35) suggesthat this phenomenon is frequent among American physi-ians and represents an important culprit working againsthe efforts to improve hypertension control rates in theopulation.

dentification and Reversalf Pseudo-Resistance Causes

easonable algorithms to identify people with pseudo-esistant hypertension have been proposed (12,13). In gen-ral, these approaches adopt a 2-step approach: first, con-rmation of true resistance (by simultaneous recognitionnd correction of factors related to pseudo-resistance); andecond, identification of the factors that contribute toreatment resistance in a given patient (Table 2).

The first step to rule out resistant hypertension is confir-ation of the diagnosis with reliable office BP readings; the

bserver should strictly follow the relevant BP measurementuidelines (20). Particular attention should be paid to theatient’s posture, environment, and triple BP readings withdequate intervals between. Additionally, use of appropriateuffs and devices is mandatory. Adherence to the recom-

actors Contributing to Resistant Hypertension

Table 2 Factors Contributing to Resistant Hypertension

Drug-induced

Nonsteroidal anti-inflammatory drugs (including cyclo-oxygenase-2 inhibitors)

Sympathomimetics (decongestants, anorectics)

Cocaine, amphetamines, other illicit drugs

Oral contraceptive hormones

Adrenal steroid hormones

Erythropoietin

Cyclosporine and tacrolimus

Licorice (included in some chewing tobacco)

Over-the-counter dietary and herbal supplements (e.g., ginseng, yohimbine,ma huang, bitter orange)

Excess alcohol intake

Volume overload

Excess sodium intake

Volume retention from kidney disease

Inadequate diuretic therapy

Associated conditions

Obesity

Diabetes mellitus

Older age

Identifiable causes of hypertension

Renal parenchymal disease

Renovascular disease

Primary aldosteronism

Obstructive sleep apnea

Pheochromocytoma

Cushing’s syndrome

Thyroid diseases

Aortic coarctation

Intracranial tumors



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ended BP measurement technique will uncover patientsho do not meet the definition of resistant hypertension.Identification of patients who have the white-coat effect

s also important. Either having qualified nonphysicianersonnel (i.e., nurses) perform office measurements orsing an automated device with the patient alone in theoom is useful. Of greater importance, however, is theetermination of BP levels under treatment with home ormbulatory measurements, again following relevant recom-endations (20,36). If BP remains elevated after this

valuation, patient adherence to therapy should be evalu-ted, as noted earlier.

actors Contributing to Resistant Hypertension

part from the aforementioned variables, a number ofiological or life-style factors can contribute to the devel-pment of resistant hypertension. Several classes of phar-acological agents can produce transient or persistent

ncreases in BP (37) (Table 3). Nonsteroidal anti-nflammatory drugs (NSAIDs) are a common cause oforsening BP control. They increase BP by an average of 5m Hg, in part because of inhibition of renal prostaglandin

roduction decreases in renal blood flow, followed byodium and fluid retention (38). They also interfere withP-lowering of all antihypertensive drug classes excepttep-by-Step Physician Guide for Evaluation andanagement of Patients Appearing to Haveesistant Hypertension

Table 3Step-by-Step Physician Guide for Evaluation andManagement of Patients Appearing to HaveResistant Hypertension

A. Become familiar with and adhere to the most recent hypertension guidelines.

B. Identify and reverse “pseudo-resistance.”

1. Perform proper measurements of BP in the office, following the relevantguidelines, to confirm the diagnosis of resistant hypertension.

2. Exclude the “white-coat effect” with the use of home or ambulatory BPmeasurements.

3. Evaluate patient’s adherence to the treatment regimens; in case of pooradherence, determine the causes of it. Educate the patient on the risks ofuncontrolled hypertension and the benefits of drug treatment and motivatethe patient to work toward an appropriate BP goal.

4. Closely follow-up nonadherent patients to ensure their compliance.

C. Identify and reverse factors contributing to true resistance.

1. Specifically ask the patient about use of any pharmacological agents thatmay increase BP; in case of identification of such a substance, discontinueor minimize its use.

2. Evaluate the amount of alcohol intake and counsel the patient on thebenefits of ceasing alcohol consumption.

3. Perform a reliable evaluation of dietary salt intake and recommend sodiumrestriction to �100 mmol (2.4 g) per day.

4. Assess the degree of obesity, abdominal obesity, and physical activity andrecommend weight reduction and regular aerobic exercise (at least 30 min/day, most days of the week).

5. Evaluate the level of renal function with estimation of glomerular filtrationrate and modify treatment accordingly.

6. Perform a thorough search for secondary hypertension; if an identifiable causeis present, treat accordingly or refer the patient to a hypertension center.

D. Treat aggressively with optimal doses of appropriate antihypertensivemedications (including drug combinations) according to patientcharacteristics.

E. Refer the patient to a hypertension specialist if BP control is not achieved.

oP � blood pressure.


alcium antagonists (39,40). The effect of NSAIDs on BP isore pronounced in patients with reduced kidney function

13). Selective cyclo-oxygenase-2 inhibitors have effectsimilar to those of NSAIDs on BP control (41). Sympatho-imetic agents (nasal decongestants, anorectic pills, co-

aine, amphetamine-like stimulants), oral contraceptives,lucocorticoids, anabolic steroids, erythropoietin, and cyclo-porine are also commonly used agents that can interfereith BP control. Black licorice, included in some oral

obacco products, and herbal supplements (e.g., ma huangnd ginseng), also raise BP (12,13,16). The effect of thesegents varies; most people manifest little or no effect, butertain persons may experience severe BP elevations. Lastly,llicit drugs can be a major unappreciated cause of resistantypertension. Agents such as steroids and cocaine areommon causes of resistant hypertension.

Although modest alcohol consumption does not generallyncrease BP, larger amounts (3 or more drinks/day) have aose-related effect on BP, both in hypertensive and normo-ensive persons (11). Alcohol intake in all hypertensiveatients should be limited to no more than 1 oz of ethanolday in most men (the equivalent of 2 drinks) and 0.5 oz of

thanol a day in women and lower-weight persons (11).A key factor responsible for many cases of resistant

ypertension is excess dietary salt intake leading to volumeverload (16). Data from small studies demonstrate that0% of patients with resistant hypertension have expandedlasma volume (42). Excessive dietary sodium intake isidespread in the U.S. and other developed countries, withrocessed foods being the most common source (13,16).he majority of patients with resistant hypertension haveigher salt intake than the general population, with anverage dietary sodium intake exceeding 10 g/day (43).

The optimal way to assess sodium intake is to measureodium excretion in a 24-h urine collection. Dietary salteduction to �3 g/day is associated with modest BPeductions, which are larger in African-American and el-erly patients (44). Current guidelines suggest that dietaryodium for a hypertensive person should be �100 mmol/ay (2.4 g sodium or 6 g sodium chloride) (11). Thisuidance is applicable to all patients with resistant hyper-ension, whereas for salt-sensitive patients, even lowermounts of sodium may be necessary.

Perhaps the most common unappreciated medical causef resistant hypertension is the presence of renal parenchy-al disease. Kidney disease is the most common secondaryedical cause of hypertension. Failure to appreciate this

elationship may lead to less than optimal choices ofntihypertensive agents such as failure to use appropriatelyosed or selected diuretics based on kidney function. This

ack of diuretic use has been shown in referral practices to behe primary cause of resistant hypertension, with the use ofhese agents helping to achieve BP goals (31).

Obesity is also a very common feature of patients withesistant hypertension (45,46). The mechanisms by which
besity contributes to BP elevation and interferes with BP


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ontrol are complex and not fully understood. Insulinesistance and hyperinsulinemia, impaired sodium excre-ion, increased sympathetic nervous system activity, in-reases in aldosterone sensitivity related to visceral adiposity,nd obstructive sleep apnea have all been implicated asotential causes (47–49).Weight loss achieved with both an appropriate exercise

rogram and a reduced calorie diet is associated with modestP reductions in obese hypertensive patients (12,13). These

eductions are greater in patients already receiving antihyper-ensive therapy (50).

Increasing age, namely, �65 years old, is associated withhigher prevalence of resistant hypertension (16,51). In-

reasing age is associated with a higher prevalence of arterialtiffening, which is not only responsible for falsely elevatedystolic BP readings but also a major cause of true elevations11,16). Current guidelines for systolic BP goals of �140 mm

g are more difficult to achieve in patients with isolatedystolic hypertension (11) and are more difficult with increasingge because of the natural history of arteriosclerosis.

Finally, in patients with resistant hypertension, the presencef secondary hypertension must be considered; although itsrevalence is largely unknown, previous studies have shownhat �5% to 10% of patients with resistant hypertension haven identifiable cause (52,53). As already mentioned, renalarenchymal disease must be considered with the strict sense ashe most common medical cause of secondary hypertension12,16). Renal arterial disease, primary aldosteronism, andbstructive sleep apnea are other common identifiable causes,hereas less common forms of secondary hypertension includeheochromocytoma, Cushing’s syndrome, hyperparathyroid-sm and hypoparathyroidism, aortic coarctation, and intracra-ial tumors (Table 3). The possibility of an identifiable cause ofypertension increases with age: renal disease, sleep apnea, andossibly primary aldosteronism are more prevalent amonglder patients (13,54).

Patients with documented resistant hypertension shoulde evaluated for secondary hypertension if indicated bylinical and routine laboratory evaluation (11). Descriptionf the signs and symptoms, diagnostic procedures, andreatment of identifiable causes of hypertension is beyondhe scope of this article (13).

harmacological Treatmentf Resistant Hypertension

uboptimal dosing regimens or inappropriate antihyperten-ive drug combinations are the most common causes ofesistant hypertension (52,53). Recommendations on theodification and intensification of antihypertensive regi-ens for a given patient taking 3 or more drugs is based on

harmacological principles in the context of the underlyingathophysiology that portends hypertension, clinical expe-ience, and available treatment guidelines.

The present rationale for intervention in resistant hyper-
ension (Fig. 2) is to ensure that all possible mechanisms for B

P elevation are blocked. As volume expansion seems theost frequent pathogenic finding in these patients (42,55),

n appropriate diuretic to decrease volume overload remainscornerstone of therapy (12,16,56). Studies suggest that

hanges in diuretic therapy (adding a diuretic, increasing theose, or changing the diuretic class based on kidney func-ion) will help �60% of these patients achieve BP goals12,42,53,55–57). Thiazide diuretics are effective fromoses of 12.5 mg/day given that kidney function is normal;ncreases up to 50 mg may provide additional BP reductionn some patients (12). Of note, there are differences betweenhiazide and thiazide-type diuretics (13,14,58). A recentrial comparing hydrochlorothiazide 50 mg and chlorthali-one 25 mg daily demonstrated that the latter providedreater ambulatory BP reduction, with the largest differenceccurring overnight (59). Additionally, a small study ofatients with resistant hypertension demonstrated thatwitching from the same dose of hydrochlorothiazide tohlorthalidone resulted in an additional 8 mm Hg drop inystolic BP and increased the number of subjects at goal60). Unfortunately, chlorthalidone is not commonly avail-ble in fixed-dose combinations; therefore, its use willequire separate prescriptions.

The most crucial part of diuretic therapy is to know whenidney function has deteriorated, so that one may select theroper class of diuretic. For thiazides, this deterioration isenerally thought to have occurred when the estimatedlomerular filtration rate (eGFR) falls to �50 ml/min/1.732; chlorthalidone can still be effective to an eGFR of �40l/min/1.73 m2 if hypoalbuminemia or hyperkalemia is not

resent. For patients with eGFR �40 ml/min/1.73 m2, aoop diuretic should be used (12,13,16). Furosemide orumetanide must be given twice daily, and possibly thriceaily in some cases, as they have short durations of action ofto 6 h. Thus, once-daily use is associated with intermittentatriuresis and consequent reactive sodium retention medi-ted by increases in the RAS (12,16,61). The loop diureticorsemide has a longer duration of action and may be givennce or twice daily (12).Use of the other drug classes in patients with resistant

ypertension should be based on the general principles ofombination therapy, namely, inhibition of different patho-enic mechanisms, choice of drugs that will compensate forossible pathophysiological changes evoked by the firstrug, and consideration of compelling indications (11,12).oreover, the Food and Drug Administration has recently

pproved 3 fixed-dose combination antihypertensive agentsor use as first-line therapy (62). These combinations allave an agent that blocks the RAS. Fixed-dose antihyper-ensive combinations are also very useful for patients withesistant hypertension, especially for those with adherenceroblems (63,64).Ultimately, patient characteristics (age, probable patho-

enic mechanisms involved, and concomitant diseases) willetermine the best combination of agents needed to achieve
P goal. In general, most patients should be on a blocker of


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he RAS along with a calcium antagonist and an appropri-tely dosed diuretic. In this case, the physician must ensurehat these agents are prescribed in full dosages, especially foratients with increased weight, and for appropriate timentervals. If BP remains above goal, the next step is to addfourth agent; a vasodilating beta-blocker is a good choice

f pulse rate is not too low. Peripheral alpha-blockers areell tolerated and can be used if the beta-blocker selectedoes not have alpha-blocking activity.For true resistant hypertension, there are also good data

o support adding a complementary calcium antagonist to aegimen including a RAS blocker, diuretic, and calcium-hannel blocker (CCB); for example, adding long-actingiltiazem to nifedipine XL. Such a combination of comple-entary CCBs results in additive BP reduction with a low

ide effect profile and makes pharmacological sense (65,66).Combining an angiotensin-converting enzyme (ACE)

nhibitor with an angiotensin receptor blocker (ARB) doesot make sense as it was recently shown to be less effective

n terms of BP reduction than was adding a diuretic or aCB to an ARB (67), was shown not to reduce cardiovas-

ular or renal events to any greater extent than individual

Figure 2 An Approach to Achieving BP Goal in Resistant Hyper

*Refers to chlorthalidone as the diuretic preferred by the guidelines, namely, thiazeffects than traditional beta-blockers such as atenolol, and also have outcome da¶Refers to physicians who are board-certified clinical hypertension specialists. BPRAS � renin-angiotensin system.

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n a separate trial, the combination of a renin inhibitoraliskiren) with an ARB was also associated with a smalldditional BP drop (70). Thus, dual RAS blockade is notecommended for patients with resistant hypertension.

Aldosterone is also part of the RAS, and specificlockade of aldosterone should be considered in certainettings. Recent studies suggest that adding spironolac-one or eplerenone to existing antihypertensive regimens foratients with resistant hypertension who are obese or haveleep apnea provides significant BP reduction (13,71). For6 patients with uncontrolled BP taking an average of 4ntihypertensive medications, the addition of spironolac-one (12.5 to 25 mg daily) resulted in an average 25/12 mm

g reduction after 6 months (72). Reductions in BP wereimilar in patients with and without primary aldosteronismnd were not predicted by baseline plasma or 24-h urinaryldosterone, plasma renin activity, or plasma aldosterone/enin ratio. These data were confirmed by a recent report of,411 participants in the Anglo-Scandinavian Cardiac Out-omes Trial—Blood Pressure Lowering Arm who werenselected for plasma aldosterone and renin activity (73)nd who received spironolactone as a fourth-line antihyper-

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e. **Vasodilating beta-blockers such as carvedilol and nebivolol have fewer sideeart disease; therefore, they are suggested for better patient adherence.d pressure; CCB � calcium-channel blocker; CKD � chronic kidney disease;

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f 3 drugs. Use of spironolactone resulted in a BP drop of1.9/9.5 mm Hg that was unaffected by age, sex, smoking,nd diabetic status. Breast tenderness with spironolactone isommon at doses above 25 mg/day but can be avoided withhe use of the more selective mineralocorticoid receptorntagonist, epleronone (14). Epleronone also has demon-trated BP-lowering efficacy as well as benefits on kidneyisease progression (74).Amiloride is another potassium-sparing diuretic associ-

ted with BP reductions in patients with resistant hyper-ension (75). When physicians prescribe these agents, espe-ially in combination with an ACE inhibitor or an ARB,hey should monitor potassium levels closely if kidneyunction is not within the normal range, and educate theatient to avoid food and supplements rich in potassium, asyperkalemia is a potentially dangerous side effect (14,76).If BP control is still not achieved with full doses of a

-drug combination, use of other agents such as centrally-cting alpha-agonists (methyldopa and clonidine) or vaso-ilators (hydralazine or minoxidil) is needed. These agentsre very effective for lowering BP, but have poor tolerabilitynd lack of positive outcome data (11). It must be noted,owever, that if therapy has progressed to adding a fourthgent, referral to a clinical hypertension specialist is war-anted (33).

Another class of agents that may prove useful for resistantypertension is endothelin-receptor antagonists (ERAs). Inatients with mild-to-moderate essential hypertension, bothonselective and selective (type A receptor) ERAs produceP reductions comparable to those of common antihyper-

ensive agents (77), but concerns about adverse eventsrecluded their use as a treatment option for uncomplicatedypertension (78). However, darusentan, a selective ERAecently tested in 115 patients with resistant hypertension,emonstrated a dose-dependent decrease in BP. The largesteductions (11.5/6.3 mm Hg) were observed after 10 weeksf follow-up with the largest dose, and the drug wasenerally well tolerated (78). Ongoing phase III clinicalrials with such agents are awaited to provide furthernformation in this interesting field.

onclusions

lthough the number of patients who cannot achieve BPoals on a regimen of multiple medications is growing, thehenomenon of resistant hypertension is widely understud-ed, a fact that requires treatment recommendations beased on pathophysiological principles and clinical experi-nce. Effective management of resistant hypertension re-uires, first, a careful examination for and exclusion ofactors associated with pseudo-resistance, and second, iden-ification and, when possible, modification of factors relatedo true BP elevations. After all of these are successfullyanaged, an aggressive treatment regimen designed to

ompensate for all mechanisms of BP elevation in a given
atient, most importantly to control volume overload with

roper use of diuretics, will help in moving toward effectiveP control for the majority of patients.

eprint requests and correspondence: Dr. George L. Bakris,ypertensive Diseases Unit, University of Chicago Pritzker

chool of Medicine, 5841 South Maryland Avenue, Chicago,llinois 60637. E-mail: [email protected].

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ey Words: resistant hypertension y management y evaluation y
reatment.


doi:10.1016/j.jacc.2008.08.036 2008;52;1749-1757 J. Am. Coll. Cardiol.

Pantelis A. Sarafidis, and George L. Bakris Resistant Hypertension: An Overview of Evaluation and Treatment

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