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Hypertension Management: An Update

Quang Nguyen, DO; Joann Dominguez, MD; Loida Nguyen, PharmD; Nageshwara Gullapalli, MD

Hypertension is a significant and costly public health problem. It is a major, but modifi-
able contributor for the development of cardiovascular disease. Randomized controlled
trials have shown that controlling hypertension reduces the risk of stroke, coronary artery
disease, congestive heart failure, end-stage renal disease, peripheral vascular disease,
as well as overall mortality. The risk of developing these hypertension-related complica-
tions is continuous, starting at a blood pressure level as low as 115/75 mm Hg. Despite
the inherent health risks associated with uncontrolled hypertension, elevated blood pres-
Quang Nguyen sure remains inadequately treated in the majority of patients. This article reviews guide-
lines for optimal evaluation of hypertension and current therapeutic options available to combat this com-
mon yet pervasive disease. [AHDB. 2010;3(1):47-56.]

H
ypertension affects approximately 1 of 3 adults lack of awareness or lack of effective pharmacologic
in the United States, and about 2 million new agents or lack of understanding of the role of lifestyle
cases are diagnosed each year.1,2 An additional modification. Since hypertension will develop in most
28% of the US population is afflicted with prehyperten- Americans in their lifetime,8 early preventive measures
sion, and approximately 7% of Americans are not aware and prompt management, including lifestyle and phar-
that they even have hypertension.3 Globally, hyperten- macologic options, are essential to minimize complica-
sion affects more than 1 billion people and is projected tions associated with this condition.
to reach 1.56 billion by 2025.4 It is the leading cause of
death and the second leading cause of lost disability- Patient Evaluation
adjusted life-years worldwide.4 Randomized controlled The Seventh Report of the Joint National Com-
clinical trials have shown that control of hypertension mittee on Prevention, Detection, Evaluation, and
reduces the risk of stroke, coronary artery disease, con- Treatment of High Blood Pressure (JNC-7) redefined
gestive heart failure, end-stage renal disease, peripheral hypertension and published an updated report in 2003.1
vascular disease, and mortality.1,5 The risk of developing Recognizing that the risk for cardiovascular disease
these complications is continuous, starting at a blood (CVD) and adverse outcomes exists linearly and con-
pressure (BP) level as low as 115/75 mm Hg.6 tinuously as BP rises, the JNC-7 panel established a
The total direct and indirect cost for hypertension new hypertension category called prehypertension
in the United States in 2009 is estimated at $73.4 bil- (120-139 mm Hg/80-89 mm Hg). Patients in this cate-
lion.3 Approximately 10% ($15 billion) of the US total gory are at risk for developing CVD and overt hyper-
annual drug expenditure is on antihypertensive med- tension; therefore, intensive lifestyle modifications are
ications.7 Despite these staggering costs, only 34% of strongly recommended to prevent further complica-
Americans with hypertension are at their BP goal tions. JNC-7 also combined the previous stage 2 and 3
(<140/90 mm Hg).1 The reason for this failure is multi- hypertension into just 1 stage—stage 2 hypertension.
factorial and only speculative, and not because of the Pharmacologic intervention is strongly recommended
for patients in stage 2 (Table 1).
Despite the prevalence of hypertension, approximate-
Dr Q. Nguyen is Assistant Professor, Department of ly 90% to 95% of American adults with elevated BP are
Endocrinology, Diabetes, and Metabolism, University of found to have no identifiable cause for their condition.
Nevada School of Medicine, Reno; Dr Dominguez is an
Of the 5% with known causes, renal parenchymal and
Internal Medicine Resident, California Pacific Medical Center,
San Francisco; Dr L. Nguyen is a Clinical Pharmacy renovascular diseases are the most common culprits.1
Specialist, VA Sierra Nevada Health Care System, Reno; Dr Other notable etiologies for hypertension include1:
Gullapalli is Assistant Professor of Medicine and Associate • Chronic kidney disease
Program Director, Internal Medicine Residency Program, • Coarctation of the aorta
University of Nevada School of Medicine, Reno. • Cushing syndrome

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• Obstructive sleep apnea KEY POINTS

• Medications
• Pheochromocytoma u Hypertension is a global epidemic, affecting about 1
• Primary hyperaldosteronism of 3 American adults, and about 2 million new cases
• Renovascular disease are diagnosed annually.
• Thyroid/parathyroid disease. u Evidence shows that controlling hypertension
reduces the risk of stroke, heart disease, end-stage
Screening and Diagnosis renal disease, peripheral vascular disease, and the
Hypertension screening is strongly recommended for associated costs.
all American adults older than age 18, according to the u Approximately 10% ($15 billion) of the US annual
latest recommendations from the US Preventive total drug expenditure is on antihypertensives. The
Services Task Force and the American Academy of total direct and indirect costs of hypertension in
Family Physicians.9,10 Screening should be repeated every 2009 are estimated at $73.4 billion.
2 years for patients with BP <120/80 mm Hg and annu- u Despite the many therapeutic options, most patients
ally for those with BP between 120 mm Hg to 39 mm Hg are still not at blood pressure goals. Instituting early
systolic BP and 80 mm Hg to 89 mm Hg diastolic BP.1 preventive measures is essential to minimize
The key to the diagnosis of hypertension is accurate complications associated with this costly condition.
measurements of BP. Improper hand positioning, incor-
rect BP cuff size, and insufficient time to relax (<5 min-
utes) before BP measurements are common errors that avoid the need for drug therapy. Maintaining a healthy
can lead to falsely elevated readings. At least 2 BP lifestyle, however, is not sufficient or is difficult to com-
readings of ≥140/90 mm Hg obtained at 3 different ply with, and most patients will require pharmacologic
office visits and separated by 2 to 4 weeks are needed to interventions to control their BP.
make the diagnosis of hypertension.11 When classifying
a patient’s BP to determine treatment, choose the high- Lifestyle Modifications
est category between the systolic and diastolic BP. JNC-7 endorses lifestyle modifications for all
Ambulatory BP monitoring or serial home BP meas- patients with prehypertension or hypertension. These
urements are recommended for patients suspected of modifications include weight loss, reduced sodium
having “white coat” hypertension (acute BP elevation intake, physical activity, limiting alcohol consumption,
in the clinic setting but normal BP when taken outside and incorporating the Dietary Approaches to Stop
of the physician’s office) or for those with labile or Hypertension (DASH) eating plan.1 In the PREMIER
inconsistent readings during the medical encounter. clinical trial, researchers compared the impact of com-
A medical history and physical examination are prehensive lifestyle modifications, which incorporate
necessary for all patients with hypertension. The main the JNC-7 recommendations (“established plus
goals are to look for reversible precipitating factors, the DASH” group) with behavioral modification without
presence and/or extent of end-organ damage, and the DASH (“established” group) and with an “advice-
presence of additional cardiovascular (CV) risk factors, only” group. Results showed greater reductions in sys-
such as diabetes or smoking. Laboratory testing should tolic BP and diastolic BP in the established group com-
also be obtained in all patients with hypertension. pared with the advice-only group (mean reductions
These tests should include urinalysis, hemoglobin or were 11.1 mm Hg, 10.5 mm Hg, and 6.6 mm Hg, sys-
hematocrit, basic metabolic panel, fasting lipids, and tolic BP, and 6.4 mm Hg, 5.5 mm Hg, and 3.8 mm Hg,
electrocardiogram.1 Urine microalbumin-to-creatinine diastolic BP, respectively), with the greatest reductions
ratio is an independent marker for overall CV risk and seen when DASH was also incorporated.13
should also be obtained.12
Pharmacotherapy
Treatment Strategies Drug therapy is needed if lifestyle modifications can-
The goal of hypertension treatment is to reduce BP not adequately bring BP to goal. First-line medications
to <140/90 mm Hg; however, in patients with hyper- used in the treatment of hypertension include diuretics,
tension and diabetes or renal disease, the BP goal is angiotensin-converting enzyme (ACE) inhibitors or
even lower, targeted at ≤130/80 mm Hg.1 Nonpharma- angiotensin receptor blockers (ARBs), beta-blockers,
cologic interventions should be instituted in all and calcium channel blockers (CCBs). Some patients
patients with hypertension. When used early, lifestyle will require 2 or more antihypertensive medications to
modifications can decrease other disease risks and may achieve their BP target. In newly diagnosed patients

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Table 1 Classification and Management of BP for Adults

Initial drug therapy
BP Systolic BP, Diastolic Lifestyle Follow-up Without compelling With compelling
classification mm Hga BP, mm Hga modifications recommendationb indication indication
Normal <120 and <80 Encourage Recheck in 2 y No antihypertensive Drug(s) for com-
indicated pelling indications
Prehypertension 120-139 or 80-89 Yes Recheck in 1 y
Stage 1 140-159 or 90-99 Yes Confirm within Thiazide-type diuretics Drug(s) for com-
hypertension 2 mo for most pelling indications
May consider ACE Other antihyperten-
inhibitors, ARBs, sives (diuretics, ACE
beta-blockers, CCBs, inhibitors, ARBs,
or combination beta-blockers, CCBs)
as needed
Stage 2 ≥160 or ≥100 Yes Evaluate in 1-4 wk 2-drug combination
hypertension depending on for most (usually
clinical situation thiazide-type diuretics
(evaluate and treat and ACE inhibitors,
immediately if BP ARBs, beta-blockers,
>180/110 mm Hg) or CCBs)
a
Ifthere is discrepancy between systolic and diastolic BP, the higher value determines staging. Treatment is determined by highest BP category.
b
Based on the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
ACE indicates angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; BP, blood pressure; CCBs, calcium channel blockers.
Source: Chobanian AV, et al. Hypertension. 2003;42:1206-1252.

with BP >20/10 mm Hg above goal,2 antihypertensives Recently these recommendations were challenged
or a combination hypertensive may be added immedi- by the Avoiding Cardiovascular Events Through
ately.1 To minimize side effects, a second drug with a Combination Therapy in Patients Living with Systolic
complementary mechanism of action should be added Hypertension (ACCOMPLISH) trial, which showed
before the initial drug is used in the maximum recom- that the combination of benazepril and amlodipine was
mended dosing. superior to the benazepril and hydrochlorothiazide
Table 2 outlines the many antihypertensives used combination in reducing CV events in high-risk
today. The Figure provides an algorithm for the treat- patients with hypertension.17 The difference in these
ment of hypertension. Table 3 lists the recommended studies was the use of chlorthalidone in earlier trials
drug classes according to compelling indications. and hydrochlorothiazide in ACCOMPLISH. In light of
Diuretics. Diuretics can be divided into 3 groups— this evidence, it has been suggested that the benefits
thiazides, loop, and potassium-sparing diuretics. seen in previous trials were attributed to a class effect,
Thiazides. Thiazides act by inhibiting the absorption when in fact hydrochlorothiazide does not provide the
of sodium and chloride in the distal convoluted tubule. same benefit profile as chlorthalidone. With these data,
The benefits of thiazides for stroke, heart failure, and some clinicians have now considered chlorthalidone as
coronary artery disease (CAD) outcomes have been the preferred thiazide agent.18,19 Because of their proved
well-established in trials, such as the VA Cooperative efficacy and low cost, thiazides will continue to be
Studies in the 1960s,14 Systolic Hypertension in the favored as first-line drugs for hypertension.
Elderly Program (SHEP) in the 1980s,15 and the Anti- Loop diuretics. Loop diuretics act on the thick
hypertensive and Lipid-Lowering Treatment to ascending loop of Henle, where they selectively inhib-
Prevent Heart Attack Trial (ALLHAT) in the 1990s.16 it the luminal Na+/K+/2Cl– symporter thereby reduc-
Based on the ALLHAT results showing thiazides’ supe- ing NaCl reabsorption. Loop diuretics are highly effica-
riority to other classes of antihypertensives in terms of cious in that they target a segment of the nephron with
secondary end points and costs, the JNC-7 issued its great reabsorptive capacity.20 These agents can be used
recommendations for thiazides as first-line therapy for alone or in combination for the management of hyper-
hypertension. tension. Although thiazides are the preferred class of

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Table 2 Selected Oral Antihypertensive Drugs

Dose range, Cost for 30-
Drug mg/d Common side effects Comments day supplya
Aldosterone antagonists
Eplerenone (Inspra) 50-100 Dizziness, fatigue, GI disturbances, More specific in aldosterone blockade $127.88-$255.76
hyperkalemia, hypertriglyceridemia Contraindicated in patients at high
risk for hyperkalemia
Spironolactone (Aldactone) 25-50 CNS effects (drowsiness, lethargy, $15.99-$21.99
headache, fatigue), GI disturbances,
hyperkalemia, menstrual irregularities,
gynecomastia, mastodynia
Alpha1-blockers
Doxazosin (Cardura) 1-16 Dizziness, headache, lack of energy, $17.99-$47.98
nausea, palpitations, orthostatic
hypotension
Prazosin (Minipress) 2-20 $17.99-$67.98
Terazosin (Hytrin) 1-20 $14.45-$27.98
Alpha2-agonists
Clonidine tablets 0.1-0.8 Dry mouth, dizziness, drowsiness, Rebound hypertension with abrupt $7-$26.65
(Catapres) constipation discontinuation
Methyldopa (Aldomet) 250-1000 Drowsiness, decrease in mental acuity, First-line agent when hypertension is $6.50-$25.99
orthostatic hypotension, nasal conges- first diagnosed in pregnancy
tion, sexual difficulty, bradycardia Positive Coombs’ test
ACE inhibitors
Benazepril (Lotensin) 10-40 Hypotension, cough, hyperkalemia, Contraindicated in patients with $23.99
Captopril (Capoten) 25-100 dizziness, headache, diarrhea, nausea, bilateral renal artery stenosis $7.19-$9.40
rash (primarily captopril), alteration or
Enalapril (Vasotec) 2.5-40 loss of taste perception (primarily $12.99-$23.98
Fosinopril (Monopril) 10-40 captopril) $30-$30.99
Lisinopril (Prinivil, Zestril) 5-40 $14.89-$17.99
Moexipril (Univasc) 7.5-30 $36.99-$69.98
Perindopril (Aceon) 4-16 $65.15-$157.91
Quinapril (Accupril) 10-80 $19.99-$43.98
Ramipril (Altace) 1.25-20 $42-$123.98
Trandolapril (Mavik) 1-4 $16.65-$33.60
Angiotensin II receptor antagonists
Candesartan (Atacand) 8-32 Hypotension, hyperkalemia, dizziness, Recommended after intolerance or $67.70-$88.44
Eprosartan (Teveten) 400-800 fatigue, diarrhea failure with ACE inhibitors $92.44
Irbesartan (Avapro) 75-300 $74.85-$91.15
Losartan (Cozaar) 25-100 $58.99-$92.22
Olmesartan (Benicar) 20-40 $67.06-$75.34
Telmisartan (Micardis) 20-80 $75.20-$85.01
Valsartan (Diovan) 80-320 $79.31-$122.27
Beta-blockers
Atenolol (Tenormin) 25-100 Bradycardia, hypotension, GI distur- $5-$5.30
Bisoprolol (Zebeta) 2.5-10 bances, dizziness, fatigue, insomnia, $16.50-$35.13
heart failure, reduced peripheral
Carvedilol (Coreg) 12.5-50 circulation, impotence, depression, Approved for CHF $29.98-$32
nightmares, bronchospasm in patients Has alpha-adrenergic–blocking activity
Labetalol (Normodyne, 200-800 with asthma, masks symptoms of or Has alpha-adrenergic–blocking activity $20.99-$57.98
Trandate) potentiates hypoglycemia in patients
with diabetes, hypertriglyceridemia
Metoprolol tartrate (Lopressor) Metoprolol succinate approved for CHF $12.99-$25.98
Continued

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Table 2 Selected Oral Antihypertensive Drugs (Continued)

Dose range, Cost for 30-
Drug mg/d Common side effects Comments day supplya
Beta-blockers
Metoprolol succinate 50-100 Metoprolol succinate approved for CHF $12.99-$25.98
(Toprol XL) $25.99-$33.88
Nadolol (Corgard) 40-120 $15.99-$47.97
Propranolol (Inderal) 40-160 $8.40-$10.66
Calcium channel blockers
Dihydropyridines
Amlodipine (Norvasc) 2.5-10 Peripheral edema, palpitations, $5.33-$8
Felodipine (Plendil) 2.5-20 headache, dizziness, fatigue, nausea $37.99-$115.45
Nicardipine (Cardene SR) 60-120 $101.19-$125.99
Nifedipine (Adalat CC, 30-60 $54.19-$72.79
Procardia XL)
Nondihydropyridines
Diltiazem (Cardizem CD, 120-420 Dizziness, headache, bradycardia, Decrease AV nodal conduction $25.99-$45.66
Dilacor XR, Tiazac) hypotension, constipation, nausea, Has negative inotropic effects
Verapamil sustained-release weakness, gingival hyperplasia, edema, $25.99-$75.98
capsule (Verelan) AV block
120-480
Verapamil sustained-release $21.99-$37.98
tablet (Calan SR, Isoptin SR)
Diuretics
Loop
Bumetanide (Bumex) 0.5-2 Hyperuricemia, hypokalemia, hyper- Preferred diuretics for patients with $5.67-$19.31
Furosemide (Lasix) 20-80 glycemia, hypocalcemia, increased uri- severe chronic kidney disease/failure $4.20-$8.39
nation at onset of therapy, dizziness,
Torsemide (Demadex) 2.5-10 weakness, muscle cramps, photosensi- $9.50-$19.99
tivity, hypotension
Thiazide
Chlorthalidone 12.5-25 Similar electrolyte abnormalities as $5-$10
Hydrochlorothiazide 12.5-50 loop diuretics except for hypercalcemia, $4.80-$14.99
(Microzide, HydroDiuril) increased urination at onset of therapy,
dizziness, weakness, muscle cramps,
Indapamide (Lozol) 1.25-2.5 photosensitivity, hypotension $5-$13.99
Metolazone (Zaroxolyn) 1.25-5 $21.50-$37.37
Potassium-sparing
Amiloride (Midamor) 5-10 Hyperkalemia, GI disturbances, muscle $50.45-$100.90
Triamterene (Dyrenium) 50-100 cramps, weakness, headache, dizziness $41.99-$64.04
Renin inhibitor
Aliskiren (Tekturna) 150-300 Diarrhea, headache, dizziness, fatigue, $82.38-$101.80
cough
Vasodilators
Hydralazine (Apresoline) 25-100 Tachycardia, palpitations, GI distur- $7.80-$27.98
bances, headache
Minoxidil (Loniten) 2.5-80 Tachycardia, hypertrichosis, sodium and $10-$143.97
water retention
a
Cost calculated from generic, if available, and lowest bottle size available. Cost source: www.drugstore.com.
ACE indicates angiotensin-converting enzyme; AV, atrioventricular; CHF, congestive heart failure; CNS, central nervous system; GI, gastrointestinal.
Sources: Lacy CF, Armstrong LL, Goldman MP, eds. Drug Information Handbook. 17th ed. Hudon, OH: Lexi-Comp; 2008; AHFS Drug Information. Bethesda,
MD: American Society of Health-System Pharmacists; 2008.

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Figure Treatment Algorithm for Hypertension inhibitor or ARB because clinically significant hyper-
kalemia can occur.
Average of ≥2 seated BP ACE inhibitors. ACE inhibitors exert their BP-low-
readings is not at goal ering effects by inhibiting the conversion of the inac-
(<140/90 mm Hg) tive angiotensin I to the active angiotensin II. In addi-
tion, bradykinins and subsequently prostaglandins are
For patients with
diabetes or chronic increased, which contributes to ACE inhibitor BP-low-
kidney disease goal BP ering effects.24 JNC-7 endorses the use of ACE
is <130/80 mm Hg inhibitors when any of the following compelling indi-
cations exist: heart failure, postmyocardial infarction
Lifestyle modifications +
drug therapy (MI), high risk of CAD, diabetes, chronic kidney dis-
ease, and/or stroke.21 A Cochrane search revealed no
difference in BP-lowering effects among the different
Without compelling With compelling ACE inhibitors, with BP-lowering trough levels of
indications indications –8/–5 mm Hg.25 These effects were seen at half or more
of the maximum manufacturer recommended doses.25 A
study conducted in the Durham Veterans Affairs
Stage 1 hypertension Stage 2 hypertension Initiate drug(s) for the
Initiate thiazide-type Initiate a combination compelling indications Medical Center (VAMC) revealed greater cost-savings
diuretic. May consider of a thiazide-type (refer to Table 3) when ACE inhibitors are initially used for the manage-
ACE inhibitors, ARBs, diuretic plus ACE ment of hypertension compared with ARBs.26 Because
beta-blockers, CCBs, or inhibitor, or ARB, beta- of cost-savings, an ACE inhibitor should be tried
combination blocker, or CCB before the initiation of an ARB.
Angiotensin receptor blockers. ARBs block angio-
If BP not at goal, optimize tensin II from binding to its receptor, thereby prevent-
dosages or add drugs until ing it from causing vasoconstriction and fluid reten-
BP is achieved tion. The Ongoing Telmisartan Alone and in
Consider consultation with Combination with Ramipril Global Endpoint Trial
hypertension specialist
(ONTARGET) established that the ARB, telmisartan,
is not inferior to the ACE inhibitor in reducing CV
ACE indicates angiotensin-converting enzyme; ARBs, angiotensin receptor and renal events in high-risk patients without heart
blockers; CCBs, calcium channel blockers. failure.27 A similar effect is seen with other ARBs and
Source: Chobanian AV, et al. Hypertension. 2003;42:1206-1252.
was confirmed in a recent Cochrane search, showing
comparable BP-lowering effects between ARBs and
diuretics, loop diuretics may be preferred in patients ACE inhibitors.25 A recent cost-effectiveness analysis
with congestive heart failure, acute pulmonary edema, of ACE inhibitors and ARBs for hypertension con-
or renal disease.21 Loop diuretics are relatively inexpen- ducted in the Durham VAMC revealed ARB-initiated
sive and are available in generic forms. patients incurred an expected cost of $6271 over 10
Potassium-sparing diuretics. Potassium-sparing diuret- years compared with an ACE inhibitor–initiated
ics act on the distal and cortical collecting tubules to patient cost of $2434. This study revealed a greater cost
decrease sodium reabsorption by either blocking aldos- in the initiation of ARBs whether the patient contin-
terone receptors (spironolactone, eplerenone) or by ued this class of medication, switched to an ACE
inhibiting Na+ influx through epithelium sodium ion inhibitor, or stopped either medication.26 Because the
channels in the apical membrane of the collecting ACE inhibitors are less costly, ARBs should be tried
tubule (amiloride and triamterene).20 These are mild only as an alternative when there is intolerance (ie,
diuretics and are effective in the treatment of hyper- cough or angioedema) or failure with ACE inhibitors.
tension, but are seldom used alone.21 These agents are Renin inhibitors. Aliskiren is the first agent in a
recommended as adjunct therapy in the treatment of new class of antihypertensive drugs that inhibits the
hypertension, especially when their hyperkalemic conversion of angiotensinogen to angiotensin I via
effect is desired. Through their actions on aldosterone renin inhibition. It is approved for monotherapy as well
receptors, spironolactone and eplerenone have been as in combination with other antihypertensives. One
shown to reduce morbidity and mortality in patients study has shown that aliskiren is not inferior to other
with heart failure.22,23 Caution must be taken when antihypertensive agents and is significantly superior to
these agents are used in conjunction with an ACE ramipril in reducing mean systolic BP.28 Studies have

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also demonstrated greater reductions in BP in com-

Table 3 Compelling Indications
bined therapy with other antihypertensive agents com-
pared with either agent alone.28,29 Another study even Recommended drugs
showed that aliskiren may have renoprotective effects, Compelling Beta- Aldosterone
reducing mean urinary albumin to creatinine ratio by indication Diuretic blocker ACEI ARB CCB antagonist
20% in patients with type 2 diabetes.30 However,
Heart failure x x x x x
because of cost concerns and robust clinical outcomes
of ACE inhibitors and ARBs, aliskiren is currently rec- Postmyocard- x x x
ial infarction
ommended as a second-line agent.
Calcium channel blockers. CCBs lower BP by pre- High coronary x x x x
venting the entry of calcium into vascular smooth disease risk
muscles, resulting in vasodilation and reduced vascular Diabetes x x x x x
contractility. The 2 types of CCBs are (1) dihydropy- Chronic x x
ridines, which act on peripheral blood vessels, and (2) kidney disease
nondihydropyridines, which act on cardiac muscles
and peripheral blood vessels. Randomized controlled Recurrent x x
stroke
trials have demonstrated that dihydropyridines are prevention
effective at reducing CV events, mortality, and strokes
ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin
particularly in the elderly.1,31 Nondihydropyridines are receptor blocker; CCB, calcium channel blocker.
useful in the treatment of cardiac arrhythmias. Both Source: Chobanian AV, et al. Hypertension. 2003;42:1206-1252.
types of drugs are effective as monotherapy in reducing
BP and are generally well tolerated. Recent results from In the absence of acute MI, congestive heart failure,
the ACCOMPLISH trial have shown that CCBs are and asymptomatic LVH, most experts agree that beta-
comparable first-line agents and are well tolerated blockers should not be used as first-line treatment in
when combined with another drug, especially an ACE patients with essential hypertension. Recent meta-
inhibitor.17 JNC-7 recognizes CCBs as a possible first- analyses have shown that beta-blockers, in comparison
line drug class for patients at high risk for CVD or for with other antihypertensives, are less effective in low-
those with diabetes (Table 3).1 ering BP5 and may be associated with increased risk of
Beta-blockers. Beta-blockers lower BP primarily by all-cause mortality and stroke, especially in patients
blocking beta-1 adrenergic receptors resulting in slow- older than age 60.32,33 A recent Cochrane review has
er heart rate, decreased cardiac contractility, and evaluated 13 randomized controlled trials to quantify
reduced cardiac output.24 As a result, beta-blockers are the efficacy and safety of beta-blockers as first-line
considered first-line medications in patients with acute therapy for essential hypertension, concluding that
MI. Beta-blockers also inhibit renin release and subse- beta-blockers are not effective first-line hypertensive
quently angiotensin II production and are therefore drugs.34 More important, there was “a trend towards
useful in the treatment of hypertensive patients with worst outcomes in comparison with calcium channel
congestive heart failure and/or with asymptomatic left blockers, renin-angiotensin system inhibitors, and thi-
ventricular hypertrophy (LVH).1 azide diuretics.”34
Clinical differences to consider when selecting an Alpha-blockers. Alpha-blockers lower BP by block-
individual beta-blocker are beta-receptor selectivity and ing vasoconstricting alpha-1 adrenoreceptors on vascu-
intrinsic sympathomimetic activity (ISA). Beta-blockers lar smooth muscles. They are beneficial in hypertensive
(ie, atenolol, bisoprolol, and metoprolol) with a greater men with benign prostate hypertrophy; otherwise, they
affinity to beta-1 receptors (heart) than beta-2 receptors are not recommended for initial monotherapy. In
(lungs, kidneys, and vasculature) are considered cardio- ALLHAT, doxazosin was associated with increased risk
selective. Nonselective beta-blockers have affinity to for CV events compared with chlorthalidone.16
beta-1 and beta-2 receptors and may not be the preferred Direct vasodilators. Hydralazine and minoxidil are
agents when treating a CV indication. Some beta-block- 2 common agents in this class. Both directly relax vas-
ers (ie, labetalol, carvedilol) also have an alpha recep- cular smooth muscle, primarily arterioles, through dif-
tor–blocking component, thus increasing its BP-lower- ferent mechanisms of action. Although both are effec-
ing capabilities. Beta-blockers with ISA (ie, pindolol) tive antihypertensive medications, their side-effect
have some stimulatory effects on the receptors they profiles preclude their use as initial monotherapy
block, but less than a pure agonist. These agents are pre- agents or as first-line therapies and make them useful
ferred when bradycardia is a concern. only as add-on therapy, especially in patients with

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severe hypertension or renal insufficiency. They are tions (inclusive of over-the-counter or nonprescribed
often prescribed in combination with a beta-blocker drugs, such as decongestants, or nonsteroidals), excess
and a diuretic to negate side effects, such as reflex alcohol consumption, excess dietary sodium intake,
tachycardia and fluid retention. Minoxidil is given obesity, diabetes mellitus, and older age. Causes of sec-
once a day, but diffuse hair/facial hair growth (hir- ondary hypertension must also be sought. If a cor-
sutism) minimizes its use in women. Hydralazine is rectable cause is not identified, the next step is to ini-
effective in the treatment of hypertensive emergencies. tiate aggressive pharmacologic therapy, with a goal of
A severe but less frequent adverse event that may blocking all possible mechanisms of BP elevation.
potentially occur with chronic hydralazine use is drug- The cornerstone of therapy is the use of diuretics,
induced systemic lupus erythematosus, which is because plasma expansion is a common pathophysio-
reversible with discontinuation of the medication. logic mechanism to resistance.35,36 Consideration of kid-
ney function is required when selecting an optimal
Combination Therapy diuretic as ineffectiveness is seen when thiazides are
Combination therapy is beneficial and should be ini- used in patients with an estimated glomerular filtration
tiated when BP is more than 20/10 mm Hg above goal.1 rate (eGFR) <30 mL/min. At lower eGFR values, loop
Most combination therapies utilize antihypertensive diuretics may be used.36 Choice of other agents should
agents that act by different but complementary mecha- be based on patient characteristics, which includes
nisms to maximize BP-lowering effects. Advantages of concomitant disease states (Table 3).
fixed combination therapy include better compliance, A fourth agent may be added if goal BP is still not
fewer side effects, faster response, and possibly lower achieved. There is evidence that the addition of
cost, depending on the choice of agents and the insur- spironolactone may have significant BP reductions, as
ance programs. seen in the Anglo-Scandinavian Cardiac Outcomes
The combination of an ACE inhibitor or ARB with Trial-Blood Pressure Lowering Arm (ASCOT-BPLA)
a diuretic is an effective and well-tolerated initial regi- with a reduction of BP as much as 21.9/9.5 mm Hg that
men. The ACCOMPLISH trial recently demonstrated was unaffected by sex, age, smoking, or diabetes status.37
that the combination of a CCB plus an ACE inhibitor Other studies show similar reductions in persons with
is also very effective.17 Concurrent use of an ACE and without hyperaldosteronism.36 The addition of
inhibitor and an ARB is not a preferred combination, spironolactone should be considered in patients who
although rarely used in heart failure or in diabetes are obese or have sleep apnea, because these conditions
patients with significant proteinuria; one should be have been associated with aldosterone excess.38
cautious about increased risk of side effects, as con- Eplerenone is an alternative aldosterone antagonist
firmed by the ONTARGET study.27 In ONTARGET, if adverse events are experienced with spironolactone.
patients receiving a combination of an ACE inhibitor Failure of a 4-drug regimen may require referral to a
and an ARB had significantly greater risk of hypoten- hypertension specialist. Less favorable options before
sion, syncope, renal dysfunction, and hyperkalemia. referral include centrally acting alpha-agonists (cloni-
Other less-effective combinations include beta-block- dine and methyldopa) or vasodilators (hydralazine and
ers/ACE inhibitors, beta-blockers/alpha-blockers or minoxidil).
agonists, and beta-blockers/nondihydropyridines.
Conclusion
Resistant Hypertension Hypertension is a global epidemic, yet many guide-
Resistant hypertension is the failure to achieve goal lines and pharmacologic options are available to pre-
BP despite adherence to 3 antihypertensive agents, vent the morbidity and mortality associated with this
including a diuretic at maximal tolerated doses.1,21 An disease. Although lifestyle modifications are frequently
approach to managing resistant hypertension includes neglected, they should be started early and continued
reevaluating factors that may contribute to lack of BP indefinitely. Some patients will require more than 1
control and aggressive use of antihypertensive agents at antihypertensive agent to control their BP. Combina-
maximal tolerated doses. Factors that may contribute tion therapies are effective and are recommended in
to uncontrolled hypertension include suboptimal BP patients with stage 2 hypertension. Regardless of which
measurement technique, white-coat effect, poor adher- drug is used, the most important aspect of treating
ence, and inappropriate dosing. Patients who are iden- hypertension is reducing BP to goal. Effective commu-
tified as having these factors are considered as having nication between physicians, other healthcare profes-
pseudoresistance. Factors that contribute to hyperten- sionals, and patients is paramount in the successful
sion, as well as resistant hypertension, include medica- treatment of hypertension. ■

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Hypertension Management

References 19. Ernst ME, Carter BL, Basile JN. All thiazide-like diuretics are not chlorthali-
done: putting the ACCOMPLISH study into perspective. J Clin Hypertens
1. Chobanian AV, Bakris GL, Black HR, et al; for the National Heart, Lung, and
Blood Institute. Seventh Report of the Joint National Committee on Prevention, (Greenwich). 2009;11:5-10.
Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 20. Jackson EK. Diuretics. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman &
2003;42:1206-1252. Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. Columbus, OH:
2. Centers for Disease Control and Prevention. High blood pressure. www.cdc. McGraw-Hill Professional; 2005:737-770.
gov/bloodpressure/. Accessed March 21, 2009. 21. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint
3. Lloyd-Jones D, Adams R, Carnethon M, et al; for the Writing Group Members. National Committee on Prevention, Detection, Evaluation, and Treatment of
Heart Disease and Stroke Statistics 2009 Update: a Report from the American High Blood Pressure: the JNC 7 Report. JAMA. 2003;289:2560-2572. Erratum:
Heart Association Staistics Committee and Stroke Statistics Subcommittee. JAMA. 2003;290:197.
Circulation. 2009;119:e21-e181. 22. Pitt B, Zannad F, Remme WJ, et al; for the Randomized Aldactone Evaluation
4. Alcocer L, Cueto L. Hypertension, a health economics perspective. Ther Adv Study Investigators. The effect of spironolactone on the morbidity and mortality in
Cardiovasc Dis. 2008;2:147-155. patients with severe heart failure. N Engl J Med. 1999;341:709-717.
5. Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with vari- 23. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone block-
ous antihypertensive therapies used as first-line agents: a network meta-analysis. er, in patients with left ventricular dysfunction after myocardial infarction. N Engl
JAMA. 2003;289:2534-2544. J Med. 2003;348:1309-1321.
6. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood 24. Hoffman BB. Therapy of Hypertension. In: Brunton LL, Lazo JS, Parker KL,
pressure to vascular mortality: a meta-analysis of individual data for one million eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed.
adults in 61 prospective studies. Lancet. 2002;360:1903-1913. Columbus, OH: McGraw-Hill Professional; 2005:845-868.
7. Spurgeon D. NIH promotes use of lower cost drugs for hypertension. BMJ. 25. Heran BS, Wong MM, Heran IK, Wright JM. Blood pressure–lowering effica-
2004;328:539. cy of angiotensin receptor blockers for primary hypertension. Cochrane Database
8. Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing Syst Rev. 2008;(4):CD003822.
hypertension in middle-aged women and men: the Framingham Heart Study. 26. Powers B, Datta S, Oddone E. A cost-effectiveness analysis of ACE-inhibitors
JAMA. 2002;287:1003-1010. vs. angiotensin receptor blockers for the treatment of hypertension. Presented at
9. US Preventive Services Task Force. Screening for high blood pressure: US the Health Service Research and Development Service 2009 national meeting,
Preventive Services Task Force reaffirmation recommendation statement. Ann February 11-13, 2009; Baltimore, MD. Abstract 1049.
Intern Med. 2007;147:783-786. 27. Yusuf S, Teo KK, Pogue J, et al; for the ONTARGET Investigators.
10. American Academy of Family Physicians. Recommendations for clinical pre- Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J
ventive services: high blood pressure. www.aafp.org/online/en/home/clinical/exam/ Med. 2008;358:1547-1559.
f-j.html. Accessed April 11, 2009. 28. Uresin Y, Taylor AA, Kilo C, et al. Efficacy and safety of the direct renin
11. The Sixth Report of the Joint National Committee on Prevention, Detection, inhibitor aliskiren and ramipril alone or in combination in patients with diabetes
Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157: and hypertension. J Renin Angiotensin Aldosterone Syst. 2007;8:190-198.
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12. Forman JP, Brenner BM. Hypertension and microalbuminuria: the bell tolls for provides additive antihypertensive efficacy when used in combination with
thee. Kidney Int. 2006;69:22. hydrochlorothiazide. J Hypertens. 2007;25:217-226.
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lifestyle modification on blood pressure control: main results of the PREMIER clin- type 2 diabetes and nephropathy. N Engl J Med. 2008;358:2433-2446.
ical trial. JAMA. 2003;289:2083-2093. 31. Neal B, MacMahon S, Chapman N; for the Blood Pressure Lowering
14. Effects of treatment on morbidity in hypertension. Results in patients with Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists,
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drug treatment in older persons with isolated systolic hypertension. Final results of the choice? Lancet. 2004;364:1684-1689.
Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-3264. 33. Medical Research Council trial of treatment of hypertension in older adults:
16. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research principal results. MRC Working Party. BMJ. 1992;304:405-412.
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angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: 35. Moser M, Setaro J. Resistant or difficult-to-control hypertension. N Engl J Med.
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Trial (ALLHAT). JAMA. 2002;288:2981-2997. 36. Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and
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STAKEHOLDER PERSPECTIVE
Hypertension Management: Implications to Patients, Providers, and Payers
PATIENTS: Hypertension, a common health tion, heart failure, chronic kidney disease, and
problem, increases with age. Based on the 2005-2006 peripheral arterial disease—all preventable with
National Health and Nutrition Examination Survey blood pressure (BP) control. Normalization of BP can
data, nearly 30% of US adults have hypertension. be achieved through lifestyle modification involving
Left untreated, the patient with hypertension is at diet, exercise, and weight reduction, or with medica-
risk for organ damage that may result in cerebrovas- tions, and often a combination.
cular disease, vascular dementia, myocardial infarc- Patients expect medications to be effective, have

Continued

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CLINICAL

STAKEHOLDER PERSPECTIVE (Continued)

minimal to no adverse effects, and be affordable. PAYERS: Because hypertension often entails
Studies suggest that combination tablets are effective medication use, payers’ interest in hypertension is
and that reduced dosing frequency improves patient naturally directed toward medication cost-contain-
adherence. In one study, barriers to adherence to ment. Controlling hypertension can minimize both
antihypertensive medications included the following clinical complications and hospitalizations, with
reasons, in this order1: their attendant high costs. The choice of generics
• Failure to remember versus brand-name drugs is always an issue. In hyper-
• Cost tension, several medications, especially the thiazides,
• Lack of health insurance are available in effective and inexpensive generic for-
• Side effects mulations. The increasing use of generics has helped
• Feeling that medications were unnecessary the national health expenditures favorably.4 Finally,
• Not having a healthcare provider. the majority of hypertensive patients will only
PROVIDERS: Physicians’ understanding of hyper- require low-cost evaluation, consisting of basic labo-
tension management is paramount to BP control. ratory tests, a chest x-ray, and an electrocardiogram.
Physicians need to understand the reasons why Such an evaluation is worth its cost, because it can
patients do not take their medications as recom- lead to favorable clinical outcomes, thereby lowering
mended, and why at times they do not even fill their healthcare costs.
prescriptions. Providers also need to evaluate the rea- From each stakeholder’s perspective—patients,
sons for hypertension resistance to therapy. The most providers, and payers—it is appropriate to expect
common reason for resistance is the failure of appro- simple, effective, adverse effect–free, and affordable
priate use of a diuretic, despite many trials showing care for hypertension, a condition that is easily treat-
that diuretics help control BP and improve outcomes able and its complications preventable.
in hypertension.2 Diuretics are inexpensive agents
and are relatively easy to use. Although diuretics and References
1. Vawter L, Tong X, Gemilyan M, Yoon PW. Barriers to antihypertensive med-
beta-blockers have been used for decades, diuretics ication adherence among adults—United States, 2005. J Clin Hypertens
(Greemwich). 2008;10:922-929.
are likely to remain as first-line agents; in contrast, 2. Ernst ME, Moser M. Use of diuretics in patients with hypertension. N Engl J
the use of beta-blockers as primary agents for hyper- Med. 2009;361:2153-2164.
3. Che QI, Schreiber MJ, Rafer MA. Beta-blockers for hypertension: are they
tension may yet be reconsidered in future, except for going out of style? Cleve Clin J Med. 2009;76:533-542.
compelling indications (eg, hypertension with coro- 4. Buffery D. Recent slowdown in national health expenditures attributed to
growing use of generics. Am Health Drug Benefits. 2009;2:25-26.
nary artery disease).3 In addition, providers may
anticipate a shift within the beta-blockers class in
favor of novel beta-blockers with vasodilatory prop- Lekshmi Dharmarajan, MD, FACP, FACC
erties. The Eighth Joint National Committee guide- Chief, Division of Cardiology, Lincoln Medical
lines for hypertension are expected to come out soon and Mental Health Center, Bronx, New York
and may provide new insights into the management Associate Professor of Clinical Medicine
of hypertension. Weill Medical College of Cornell University, NY

56 I AMERICAN HEALTH & DRUG BENEFITS I January/February 2010 VOL. 3 I NO. 1