030213 initial treatment of hypertension

The new england journal of medicine This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations. A 50-year-old black American has a blood pressure of 160/110 mm Hg on repeated
measurements. He is 9 kg (20 lb) overweight, has a family history of hypertension, and
smokes one pack of cigarettes daily. How should this patient be evaluated and treated?

From Weill Medical College of Cornell Uni- Hypertension (systolic pressure ≥140 mm Hg or diastolic pressure ≥90 mm Hg) is versity and the Lang Research Center, New present in one in four adults in the United States.1 The prevalence is higher among York Hospital Medical Center of Queens — blacks and older persons, especially older women. Table 1 shows the classification of blood pressure according to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.2 Hypertension is a risk factor for Copyright 2003 Massachusetts Medical Society. stroke, myocardial infarction, renal failure, congestive heart failure, progressive ath-erosclerosis, and dementia.3 Systolic pressure is a stronger predictor of cardiovascularevents than is diastolic pressure,4 and isolated systolic hypertension, which is commonamong older persons, is particularly hazardous.5 There is a continuous, graded relationbetween blood pressure and the risk of cardiovascular disease; the level and duration ofhypertension and the presence or absence of coexisting cardiovascular risk factors de-termine the outcome.6 Treatment of hypertension reduces the risk of stroke, coronaryartery disease, and congestive heart failure, as well as overall cardiovascular morbidityand mortality from cardiovascular causes. However, only 54 percent of patients withhypertension receive treatment and only 28 percent have adequately controlled bloodpressure.1 s t r a t e g i e s a n d e v i d e n c e e v a l u a t i o n
Accurate measurement of blood pressure7 and verification of elevated pressure on mul-tiple occasions over time are important. Ambulatory or home blood-pressure moni-toring8 can identify “white-coat hypertension” (blood pressure that is elevated whenmeasured during an office visit but that is otherwise normal) and prevent unnecessarytreatment. White-coat hypertension, present in 20 percent of patients with elevatedblood pressure, is associated with a lower cardiovascular risk than is sustained hyper-tension, but it may be a precursor of sustained hypertension and therefore warrantsmonitoring.
In addition to the history taking and physical examination, several tests are routinely indicated in patients with hypertension: urinalysis, complete blood count, blood chem-ical tests (measurements of potassium, sodium, creatinine, fasting glucose, total choles-terol, and high-density lipoprotein), and 12-lead electrocardiography. The evaluationshould identify signs of cardiovascular, cerebrovascular, or peripheral vascular diseaseand other cardiovascular risk factors that are frequently present in patients with hyper-tension. Severe or resistant hypertension or clinical or laboratory findings suggesting Downloaded from www.nejm.org by SCHLOMO ASCHKENASY on November 28, 2004 . Copyright 2003 Massachusetts Medical Society. All rights reserved. the greater the reduction in absolute risk (and the Table 1. Classification of Blood Pressure in Adults.*
smaller the number needed to treat).
Determination of the need for drug therapy is Category
Blood Pressure
based on a combined assessment of the blood-pres- sure level and the absolute risk of cardiovascular disease (Fig. 1). Patients with stage 1 hypertensioncan be treated with lifestyle modifications alone for up to one year, if they have no other risk factors, or for up to six months, if they have other risk factors.
Drug treatment should be provided if blood pres- sure remains elevated after a trial of lifestyle modi- 160–179 Systolic or 100–109 diastolic fications alone. Lifestyle modifications and anti-hypertensive therapy are indicated for patients with * The classification is for persons 18 years of age or older who cardiovascular or other target-organ disease (renal, are not taking antihypertensive drugs and are not acutely ill. cardiac, cerebrovascular, or retinal disease) and for When systolic and diastolic pressures fall into different cate-gories, the higher category should be used to classify blood those with stage 2 or 3 hypertension. Patients with pressure. Isolated systolic hypertension is defined as a sys- diabetes are at high risk, and drug therapy is indicat- tolic pressure of 140 mm Hg or greater and a diastolic pres- ed in such patients even if blood pressure is at the sure below 90 mm Hg. Data are from the Joint National Committee on Prevention, Detection, Evaluation, and Treat- † The stage is determined on the basis of the average of two or more readings at each of two or more visits after an initial screening.
Table 2 lists lifestyle modifications recommendedfor all patients with hypertension. The DietaryApproaches to Stop Hypertension (DASH) study the presence of renal disease, adrenal hypertension showed that eight weeks of a diet of fruits, vege-(due to abnormal mineralocorticoid secretion or tables, low-fat dairy products, whole grains, poul-pheochromocytoma), or renovascular hypertension try, fish, and nuts, with limited fats, red meat, andshould be further investigated. Essential, or primary, sweets, reduced systolic pressure by 11.4 mm Hghypertension, the focus of this article, is the diagno- and diastolic pressure by 5.5 mm Hg.13 With sodi-sis in over 90 percent of cases.
um intake at a level below 100 mmol per day, systol-ic pressure was 3 mm Hg lower and diastolic pres- t r e a t m e n t
sure was 1.6 mm Hg lower than with the DASH diet The primary goal of the treatment of hypertension and a higher level of sodium intake.14is to prevent cardiovascular disease and death. Co- Restriction of sodium intake to 2 g per day low- existing cardiovascular risk factors increase the risks ers systolic pressure, on average, by 3.7 to 4.8 mm Hgassociated with hypertension and warrant more ag- and lowers diastolic pressure, on average, by 0.9 togressive treatment. The five-year risk of a major car- 2.5 mm Hg,15,16 although the reductions vary fromdiovascular event in a 50-year-old man with a blood person to person beyond these ranges. Salt sensitiv-pressure of 160/110 mm Hg is 2.5 to 5.0 percent; the ity is common in elderly patients with hypertension.
risk doubles if the man has a high cholesterol level Despite concern that salt restriction for all patientsand triples if he is also a smoker.9 with hypertension might have adverse consequenc- The benefits of lowering blood pressure, first es,17 moderate sodium restriction appears to be demonstrated after short-term treatment of malig- generally safe and effective18 and is particularly ef-nant hypertension,10 have subsequently been dem- fective in elderly persons.19onstrated in all stages of hypertension. Trials involv- Whether lifestyle modifications can be sustained ing patients with stage 1 or 2 hypertension showed is a concern. Four years after enrollment in the Treat-that lowering systolic pressure by 10 to 12 mm Hg ment of Mild Hypertension Study, patients withand diastolic pressure by 5 to 6 mm Hg reduces the stage 1 hypertension had gained back half therisk of stroke by 40 percent, the risk of coronary dis- weight lost after one year of intervention and wereease by 16 percent, and the risk of death from any less successful at maintaining a low sodium intakecardiovascular cause by 20 percent.11,12 The higher and an increased level of physical activity than theythe blood pressure and the number of risk factors, had been at one year.20 Nevertheless, lifestyle mod- Downloaded from www.nejm.org by SCHLOMO ASCHKENASY on November 28, 2004 . Copyright 2003 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Figure 1. Treatment of Hypertension According to the Level of Blood Pressure and Cardiovascular Risk.
Two or more blood-pressure readings separated by two minutes should be averaged. If the pressure is at the high end of the normal range, it should be rechecked yearly. Stage 1 hypertension should be confirmed within two months. Patients with stage 2 hypertension should be eval-uated and referred for care within one month; those with stage 3 hypertension should be evaluated immediately or within one week. If systolic and diastolic values are in different categories, the recommendations for the higher reading should be followed.
Laboratory tests include a complete blood count; measurements of potassium, sodium, creatinine, fasting glucose, total cholesterol, and high-density lipoprotein cholesterol; and urinalysis. ECG denotes electrocardiography. Cardiovascular or other target-organ disease denotes left ventricular hypertrophy, angina or prior myocardial infarction, prior coronary revascularization, heart failure, stroke or transient ischemic attack, nephropathy, peripheral arterial disease, and retinopathy.
For patients with multiple risk factors, clinicians should consider drugs as initial therapy along with lifestyle modifications. Clinically impor-tant risk factors include smoking, dyslipidemia, diabetes mellitus, an age of more than 60 years, male sex, postmenopausal status in women, and a family history of cardiovascular disease for women under the age of 65 years and men under the age of 55 years. Adapted from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.2 ifications alone controlled blood pressure at four safe and inexpensive and, when combined with drugyears in 59 percent of the patients.
therapy, may result in better blood pressure control Most clinical trials of lifestyle modifications and an improved quality of life.21 have been underpowered or of insufficient dura-tion to evaluate the effect of these interventions on Treatment Goal for Blood Pressuremajor cardiovascular outcomes. However, lifestyle The risk of cardiovascular disease remains highermodifications should be encouraged, since they are in treated patients with hypertension than in per- Downloaded from www.nejm.org by SCHLOMO ASCHKENASY on November 28, 2004 . Copyright 2003 Massachusetts Medical Society. All rights reserved. sons with normal blood pressure, suggesting thattreatment targets have not been low enough. Great- Table 2. Lifestyle Modifications to Prevent or Manage Hypertension.*
er reductions in blood pressure have been shown to Modification
be safe and beneficial.22,23 In the Hypertension Op-timal Treatment trial, the risk of major cardiovascu- lar events was lowest among patients whose blood pressure had been reduced to 138.5/82.6 mm Hg.
Engage in aerobic physical activity (30 to 45 An additional reduction did not further reduce the risk of events in nondiabetic patients, but it was not Eat abundant fruits and vegetables and low-fat harmful. Among diabetic patients, the lowest rates dairy products; reduce intake of saturated of major cardiovascular events and death from car- diovascular causes were achieved with the lowest Limit sodium intake to a maximum of 100 mmol May lower blood pressure by blood pressure. In patients over the age of 65 years, per day (2.4 g of sodium or 6 g of sodium morbidity and mortality from cardiovascular dis- ease are reduced when systolic pressure is lowered Maintain adequate intake of dietary potassium to a level below 160 mm Hg.24 Whether levels be- low 140 mm Hg provide additional protection is Maintain adequate intake of dietary calcium and Limit alcohol intake to a maximum of 30 ml (1 oz) per day (15 ml [0.5 oz] per day for women and people with low body weight) Most antihypertensive drugs reduce blood pressureby 10 to 15 percent. Monotherapy is effective in about 50 percent of unselected patients, and thosewith stage 2 or 3 hypertension often need more than * Data are from the Joint National Committee on Prevention, Detection, Evaluation, one drug.25 There have been few comparative trialsof antihypertensive agents that have had sufficientpower to demonstrate an advantage of one drug major cardiovascular events, and death from car-over another, and there is individual variation in re- diovascular causes; however, these drugs do notsponsiveness to drugs. Thus, the choice of therapy significantly reduce the risk of coronary heart dis-is based on a combined assessment of several char- ease, heart failure, or death from any cause.26acteristics of the patient: coexisting conditions, age, The question of whether antihypertensive agents race or ethnic group, and the response to previous- differ in their ability to prevent adverse outcomesly used drugs, including the presence or absence of has been difficult to answer.28 Some data suggestadverse reactions.
potentially important differences. For example, ACE A critical issue is whether a drug reduces cardio- inhibitors were more effective than calcium-chan- vascular morbidity and mortality. As compared with nel antagonists in preventing coronary heart dis-placebo, diuretics and beta-blockers reduce the risk ease in one trial,29 but not in another, larger study.30of stroke, coronary heart disease, and overall mor- A meta-analysis of clinical trials suggests thattality from cardiovascular disease in unselected pa- ACE inhibitors are more effective than calcium-tients with hypertension who do not have preexist- channel antagonists in reducing the risk of hearting coronary disease, diabetes, or proteinuria.11,12 failure but not in reducing the risk of stroke, deathA meta-analysis of trials involving more than 26,000 from cardiovascular disease, or death from anypatients showed that, as compared with placebo, cause.26 Losartan, an angiotensin-receptor antago-angiotensin-converting–enzyme (ACE) inhibitors nist, has recently been shown to be more effectivereduce the risk of stroke, coronary heart disease, than atenolol in reducing the risk of stroke.31 An-major cardiovascular events, death from cardiovas- other meta-analysis suggests that calcium-chan-cular causes, and death from any cause,26 although nel antagonists may prevent stroke to a greater ex-the results were heavily dependent on a trial in tent than diuretics or beta-blockers but have notwhich all the participants had preexisting cardio- been shown to provide similar protection againstvascular disease or diabetes and some did not have coronary heart disease.32 The Antihypertensivehypertension.27 Calcium-channel antagonists, as and Lipid-Lowering Treatment to Prevent Heart At-compared with placebo, reduce the risk of stroke, tack Trial, the largest randomized trial comparing Downloaded from www.nejm.org by SCHLOMO ASCHKENASY on November 28, 2004 . Copyright 2003 Massachusetts Medical Society. All rights reserved. The new england journal of medicine several antihypertensive agents as initial therapy, medical conditions (Table 3). In particular, ACEdemonstrated that in patients older than 55 years inhibitors and angiotensin-receptor antagonists(35 percent of whom were black and 19 percent of are appropriate initial therapy in patients with di-whom were Hispanic), diuretic-based therapy was abetes mellitus, renal disease, or congestive heartas effective as treatment with calcium-channel an- failure35,36 (though beta-blockers and diuretics aretagonists or ACE inhibitors in preventing major cor- also useful in patients with heart failure); ACE in-onary events.33 Diuretic-based therapy was slightly hibitors can also be used in patients with prior my-more effective than treatment with calcium-chan- ocardial infarction or coronary artery disease. Short-nel antagonists in preventing heart failure and was acting calcium-channel antagonists cause a rapid,more effective than treatment with ACE inhibitors acute drop in blood pressure, which may precipitatein preventing stroke and heart failure. A smaller coronary ischemia, and long-acting calcium-chan-study of elderly white men and women with hyper- nel antagonists are therefore preferred when thistension, reported in this issue of the Journal, showed class of agent is chosen.37 Alpha-blockers relievethat ACE-inhibitor–based therapy was slightly more symptoms associated with prostatic hypertrophy.
effective than diuretic-based therapy in preventing Since they are not as effective as other agents inmyocardial infarction (only in men) but not stroke.34 reducing the risk of cardiovascular disease, they On the basis of the available data, diuretics or should be used as second- or third-line therapy.33 beta-blockers remain appropriate for the initialtreatment of uncomplicated hypertension, despite Other Considerations in the Choice of Therapythe concern that these agents may be associated Age and race have been shown to be determinantswith adverse metabolic effects (e.g., hyperuricemia of the response to specific antihypertensive medi-and impaired glucose tolerance). Alternative drugs cations. The Department of Veterans Affairs Coop-are preferable for patients with certain coexisting erative Study reported that younger whites had a Table 3. Indications for the Use of Antihypertensive Drugs, Contraindications, and Side Effects.*
Class of Drug
Side Effects
cose intolerance, hypercalcemia (thiazides), hyperlipidemia, hy-ponatremia, impotence (thia-zides) Asthma, chronic obstructive Bronchospasm, bradycardia, heart circulation, insomnia, fatigue, decreased exercise tolerance, hypertriglyceridemia calcium-channel antagonists may precipitate coronary ischemia * Modified from the United Kingdom Prospective Diabetes Study Group.23 ACE denotes angiotensin-converting enzyme.
Downloaded from www.nejm.org by SCHLOMO ASCHKENASY on November 28, 2004 . Copyright 2003 Massachusetts Medical Society. All rights reserved. good response to ACE inhibitors and beta-block- tients into risk categories on the basis of age, sex,ers, whereas older blacks had a better response to smoking status, presence or absence of diabetes,diuretics or calcium-channel antagonists.25 cholesterol level, presence or absence of preexist- Hypertension is more severe and target-organ ing cardiovascular disease, and presence or absence damage, particularly end-stage renal disease, more of target-organ damage (Fig. 1). Drug treatment isprevalent among blacks. Salt sensitivity is common, recommended for stage 1 or higher hypertension ifand sodium restriction should be encouraged. Al- blood pressure does not decrease after a certain pe-though the magnitude of the blood-pressure re- riod of lifestyle-modification counseling (6 to 12sponse to monotherapy with a diuretic or a calci- months, according to the Joint National Committeeum-channel antagonist may be greater than the guidelines). The British Hypertension Society andresponse to monotherapy with another agent, sig- New Zealand guidelines recommend the use ofnificant reductions occur with ACE inhibitors, an- tables that quantify a person’s 5- or 10-year risk ofgiotensin-receptor antagonists, and beta-blockers a cardiovascular event; drugs are recommended onlywhen an adequate dose is given.38 if the 5-year risk is at least 10 percent.42,43 When Side effects differ according to the class of anti- drugs are indicated, the guidelines recommend hypertensive drug (Table 3). Although adverse ef- those that have been shown to improve cardiovas-fects are reported by 10 to 20 percent of patients cular outcomes, with coexisting conditions andtaking such drugs, the quality of life improves when demographic characteristics taken into account.
hypertension is treated.21 The Treatment of MildHypertension Study and the Department of Veter- ans Affairs Cooperative Study both demonstratedthat among the five main classes of antihyperten- Although moderate sodium restriction lowers bloodsive drugs (diuretics, beta-blockers, calcium-chan- pressure, the small effects, variability in response,nel antagonists, ACE inhibitors, and alpha-block- and lack of a proven cardiovascular benefit have leders), no one drug is more acceptable than the others, to uncertainty about whether it should be broadlyexcept that sexual dysfunction is more common recommended. There is also uncertainty aboutamong men treated with the diuretic chlorthali- whether specific properties of certain drugs result indone.21,25 Use of lower-cost, generic drugs that re- differential effects on morbidity and mortality thatquire less frequent doses can improve compliance. are independent of the reduction in blood pressure.
The use of drugs in patients with a low absolute risk of cardiovascular disease is controversial. The The use of lower doses of two or more drugs with rationale for withholding drugs from such patientscomplementary mechanisms may lower blood pres- is that some trials have shown that mortality amongsure with fewer adverse effects than the use of high- low-risk patients treated with drugs is similar toer doses of a single agent.39 Most combination that in control groups.44 However, given that eventherapies include small doses of a diuretic, which high-normal blood pressures (130 to 139/85 to 89potentiate the effects of other drugs (ACE inhibitors, mm Hg) are associated with an increased risk ofangiotensin-receptor antagonists, or beta-blockers). cardiovascular disease,45 there is concern aboutCombination therapy may improve compliance and withholding drugs from “low-risk” patients. Also,achieve the target blood pressure more rapidly.40 the feasibility of basing treatment decisions on theuse of tables for calculating the absolute risk of car-diovascular disease has not been assessed.
The appropriate strategy for choosing the initial National and international groups have issued antihypertensive therapy is still unresolved. Someguidelines for the treatment of hypertension. The have proposed that the choice of treatment shouldmain differences among these guidelines are the be based on renin levels,46 but this approach is notcriteria for initiating drug therapy in low-risk pa- widely used. Whether combination therapy as thetients with stage 1 hypertension. The Joint National initial treatment leads to better control of bloodCommittee on Prevention, Detection, Evaluation, pressure and a lower risk of cardiovascular diseaseand Treatment of High Blood Pressure2 and the than monotherapy is also unresolved. Finally, opti-World Health Organization–International Society mal blood-pressure targets remain to be deter-of Hypertension41 recommend stratification of pa- mined, particularly for elderly patients.
Downloaded from www.nejm.org by SCHLOMO ASCHKENASY on November 28, 2004 . Copyright 2003 Massachusetts Medical Society. All rights reserved. The new england journal of medicine prior myocardial infarction, and calcium-channel antagonists benefit elderly patients at risk for stroke.
If blood pressure is not controlled with an optimal Hypertension affects 25 percent of adults in the dose of a single drug, a second agent with a com-United States and is adequately treated in less than plementary mechanism of action should be added.
30 percent of them. Appropriate therapy can reduce Combination therapy provides more rapid controlblood pressure and cardiovascular morbidity and of blood pressure than does monotherapy and ismortality.
therefore an initial treatment option for patients Persons who have stage 1 hypertension and are with stage 2 or 3 hypertension.
at low risk for cardiovascular disease can be treated The patient in the case vignette should be ad- with lifestyle modifications for up to one year. Pa- vised to lose weight, stop smoking, engage in reg-tients who have stage 1 hypertension and other car- ular exercise, and modify his diet and should bediovascular risk factors or a higher stage of hyper- screened for vascular disease and other cardiovas-tension should be treated with drugs to reduce blood cular risk factors. If no coexisting disease was de-pressure to a level below 140/90 mm Hg, or to re- tected, I would prescribe hydrochlorothiazide at aduce pressure to 130/80 mm Hg or less if the pa- dose of 12.5 mg daily. If this dose did not controltient has diabetes, renal disease, or both.
his blood pressure, I would increase it or add a sec- Diuretics and beta-blockers are appropriate as ond drug with complementary action — for exam- first-line therapy for patients without coexisting con- ple, an ACE inhibitor; the latter option would pre-ditions. ACE inhibitors or angiotensin-receptor an- vent the adverse metabolic effects of higher dosestagonists are recommended for patients with type of diuretics.
2 diabetes, kidney disease, or both and are also use- I am indebted to Dr. Manikkam Suthanthiran for his invaluable ful in patients with heart failure. Beta-blockers and editorial assistance.
ACE inhibitors are recommended in patients with r e f e r e n c e s
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