Hypertension Management:: An Update
Hypertension Management:: An Update
Hypertension Management:: An Update
CLINICAL
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
CLINICAL
Hypertension Management
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
CLINICAL
Hypertension Management
CLINICAL
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
Hypertension Management
CLINICAL
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. ■
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.
2413-2446. 29. Villamil A, Chrysant SG, Calhoun D, et al. Renin inhibition with aliskiren
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.
13. Appel LJ, Champagne CM, Harsha DW, et al. Effects of comprehensive 30. Parving HH, Persson F, Lewis JB, et al. Aliskiren combined with losartan in
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,
diastolic blood pressures averaging 115 through 129 mm Hg. JAMA. 1967;202: and other blood pressure–lowering drugs results of prospectively designed
1028-1034. overviews of randomised trials. Lancet. 2000;355:1955-1964.
15. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive 32. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise
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.
Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart 34. Wiysonge CS, Bradley H, Mayosi BM, et al. Beta-blockers for hypertension.
Attack Trial. Major outcomes in high-risk hypertensive patients randomized to Cochrane Database Syst Rev. 2007;(1):CD002003.
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.
the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack 2006;355:385-392.
Trial (ALLHAT). JAMA. 2002;288:2981-2997. 36. Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and
17. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or treatment. J Am Coll Cardiol. 2008;52:1749-1757.
hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008; 37. Chapman N, Dobson J, Wilson S, et al. Effect of spironolactone on blood pres-
359:2414-2428. sure in subjects with resistant hypertension. Hypertension. 2007;49:839-845.
18. Saklayen MG. Which diuretic should be used for the treatment of hyperten- 38. Goodfriend TL, Calhoun DA. Resistant hypertension, obesity, sleep apnea,
sion? Am Fam Physician. 2008;78:444,446. and aldosterone: theory and therapy. Hypertension. 2004;43:518-524.
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
CLINICAL