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Choice of therapy in essential

hypertension:
Recommendations
Authors
Norman M Kaplan, MD
Burton D Rose, MD

Section Editor
George L Bakris, MD

Deputy Editor
Alice M Sheridan,
MD

Last literature review version 17.3: September 2009 | This topic last
updated: July 23, 2009 (More)
INTRODUCTION There is no uniform agreement as to which
antihypertensive drugs should be given for initial therapy. The major options
are:
Thiazide-type diuretics
Angiotensin converting enzyme (ACE) inhibitors/angiotensin II receptor
blockers (ARBs)
Calcium channel blockers
Beta blockers, which are now used less often for initial therapy in the
absence of a specific indication for their use
Recommendations concerning the use of particular agents for the initial
treatment of hypertension will be presented here. The efficacy of these
agents, the clinical trials that examined their effects upon patient outcomes,
particularly cardiovascular morbidity and mortality, and the indications for
initiating antihypertensive therapy are discussed separately. ( See "Choice of
therapy in essential hypertension: Clinical trials" and see "Hypertension: Who
should be treated?" ).
RELATIVE EFFICACY OF ANTIHYPERTENSIVE DRUGS Each of the
antihypertensive agents is roughly equally effective in lowering the blood
pressure, producing a good antihypertensive response in 30 to 50 percent of
patients ( show figure 1 and show figure 2 ) [1-5] . There is, however, wide
interpatient variability as many patients will respond well to one drug but not
to another. ( See "Initial monotherapy" below ).
Importance of attained blood pressure Meta-analyses published in 2008
and 2009, the 2007 American Heart Association statement on the treatment

of blood pressure in ischemic heart disease, and the 2007 European Society of
Hypertension/European Society of Cardiology guidelines on the management
of hypertension all concluded that the amount of blood pressure reduction is
the major determinant of reduction in cardiovascular risk in both younger and
older patients with hypertension, NOT the choice of antihypertensive drug
[1,2,6,7] .
This conclusion was based upon the finding in a number of large randomized
trials that, at the same level of blood pressure control, most antihypertensive
drugs provide the same degree of cardiovascular protection. As an example,
the CAPPP, STOP-Hypertension-2, NORDIL, UKPDS, and INSIGHT trials found
little overall difference in outcomes between older (such as diuretics and beta
blockers) and newer antihypertensive drugs (such as ACE inhibitors and
calcium channel blockers) [ 3,8] . Similar findings have been noted in the
subgroup of patients at increased cardiovascular risk. ( See "Choice of therapy
in essential hypertension: Clinical trials" and see "Choice of antihypertensive
drug and blood pressure goal in patients at increased risk for a cardiovascular
event" ).
When differences in outcomes have been noted in trials comparing different
antihypertensive drugs, the drug producing better outcomes had better blood
pressure control. As examples:
The ASCOT trial found a lower rate of cardiovascular disease and death
with a calcium channel blocker ( amlodipine ) compared to a beta blocker
(atenolol ). However, patients in the amlodipine arm had a significantly
lower mean blood pressure at the end of the study (3/2 mmHg) [ 9] .
Ramipril and perindopril produced better outcomes than placebo in the
HOPE and EUROPA trials of patients at increased cardiovascular risk, but
the blood pressure was significantly lower in the treated patients:
3.3/1.4 mmHg (with a greater difference overnight) in HOPE and 5/2
mmHg in EUROPA [10,11] . (See "Choice of antihypertensive drug and
blood pressure goal in patients at increased risk for a cardiovascular
event" ).
In the VALUE trial, amlodipine produced better outcomes than valsartan
but also greater blood pressure reduction. When 5000 pairs were
matched exactly for systolic blood pressure and other risk factors, the
two groups had nearly identical rates of cardiovascular events [ 12] .
Possible exceptions to these general findings were thought to come from the
ALLHAT trial of monotherapy and from the ACCOMPLISH trial of combination
therapy..
ALLHAT trial The ALLHAT trial randomly assigned over 41,000 hypertensive

patients (mean blood pressure 146/84 mmHg) with at least one other
coronary risk factor to one of four initial regimens: chlorthalidone (12.5 to 25
mg/day), amlodipine , lisinopril, or doxazosin , which was prematurely
terminated due to an increased risk of heart failure [ 13] . At a mean follow-up
of 4.9 years, the primary outcome (fatal coronary heart disease and nonfatal
myocardial infarction) was the same in the three arms ( show figure 3 ) [13] .
However, the chlorthalidone arm had a significantly lower rate of heart failure
than amlodipine and lisinopril ( show figure 4 ) and a significantly lower rate of
combined cardiovascular disease outcomes than lisinopril ( show figure 5 ).
(See "Choice of therapy in essential hypertension: Clinical trials" , section on
ALLHAT trial).
It seems likely that the benefits seen with chlorthalidone were due at least in
part to an earlier and greater degree of blood pressure reduction, similar to
the findings with amlodipine in the VALUE trial described in the preceding
section [ 12] . Chlorthalidone was associated with a small but significantly
lower systolic pressure over the course of the study than amlodipine or
lisinopril (133.9 versus 134.7 and 135.9 mmHg, respectively) and a higher
proportion of patients who attained the blood pressure goal of less than
140/90 mmHg (68.2 versus 66.3 and 61.2 percent, respectively). The
difference in mean systolic blood pressure was most pronounced in the first
two years (136.4 versus 137.8 and 139.2 mmHg, respectively).
Twenty-four-hour blood pressure monitoring was not obtained in ALLHAT,
which may have been important, since chlorthalidone is long-acting, while the
effect of lisinopril may diminish toward the end of the day, especially at doses
of 10 mg/day.
The findings in ALLHAT led the Seventh Report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure
(JNC 7), which was published in 2003, and others to conclude that low-dose
thiazides (eg, hydrochlorothiazide or chlorthalidone at 12.5 mg/day) should be
used in the initial drug treatment of most patients with uncomplicated
hypertension, unless there is a specific indication for a drug from another class
(show table 1 ) [14,15] . (See "Indications for specific drugs" below ).
One cannot exclude that the observed benefits with
chlorthalidone in ALLHAT
were due at least in part to the lower attained blood pressure, which is in
keeping with the findings in other trials cited in the preceding section.
Looking at the data in another way, there was no difference in the primary
end point among the three treated groups ( show figure 3 ), despite the lower
attained blood pressure with chlorthalidone . This raises the possibility that
thiazide diuretics may actually be associated with worse outcomes at the
same attained blood pressure. Although this may seem to represent
manipulation of the data, it is an important consideration given the findings in

the ACCOMPLISH trial in which benazepril plus hydrochlorothiazide was

associated with worse cardiovascular outcomes than benazepril plus
amlodipine , despite a trend toward lower 24-hour average blood pressure in
the benazepril plus hydrochlorothiazide group. ( See "ACCOMPLISH trial"
below ).
Chlorthalidone versus hydrochlorothiazide Chlorthalidone at the same
dose is approximately 1.5 to 2.0 times as potent as hydrochlorothiazide
[16-18] . Thus, 12.5 mg/day of chlorthalidone is equivalent to 19 to 25 mg/day
of hydrochlorothiazide. This may not be so important for efficacy since the
dose-response curve for thiazide diuretics in the treatment of essential
hypertension is relatively flat ( show figure 6 ) [2,19,20] . However, metabolic
complications, such as hypokalemia, glucose intolerance, and hyperuricemia
increase with dose ( show figure 7 ) [2,19,20] . In two major trials of low-dose
chlorthalidone (12.5 to 25 mg/day), treatment for hypokalemia was required in
7 to 8 percent of patients [ 13,21] . (See "Thiazide diuretics in essential
hypertension" and see "Diuretic-induced hypokalemia" ).
A possibly more important difference than potency is the longer duration of
action of chlorthalidone (24 to 72 hours versus 6 to 12 hours with
hydrochlorothiazide ) [16,18] . This may not affect office blood pressure if the
medication is taken in the morning but may result in a greater fall in nighttime
blood pressure with chlorthalidone compared to baseline (eg, -13.5 mmHg
with 12.5 mg/day [force titrated to 25 mg/day] versus -6.4 mmHg with 25
mg/day [force titrated to 50 mg/day] of hydrochlorothiazide in a small
randomized, crossover trial) [ 17] .
The importance of the shorter duration of action of hydrochlorothiazide was
also addressed in a study in which 24-hour ambulatory monitoring was
performed in 228 patients with essential hypertension [ 22] . The mean fall in
blood pressure with ambulatory monitoring after four weeks of therapy with
hydrochlorothiazide 25 mg/day was significantly greater with office blood
pressure compared to 24-hour ambulatory measurements (14.3 versus 9.5
mmHg).
There are no randomized trials comparing outcomes in hypertensive patients
treated with hydrochlorothiazide or chlorthalidone . A meta-analysis of trials
comparing one of the two drugs to placebo concluded that the magnitude of
benefit was similar with the two drugs [ 23] . However, the daily doses used in
the trials that accounted for most of the patients in the meta-analysis were
roughly equipotent: 25 to 50 mg of hydrochlorothiazide in combination with
amiloride or triamterene and 12.5 to, if necessary, 25 mg of chlorthalidone.
Given the lower potency of hydrochlorothiazide at the same dose and its
shorter duration of action, one cannot conclude in the absence of evidence
that 12.5 mg/day of hydrochlorothiazide will produce the same cardiovascular

benefit as 12.5 mg/day of chlorthalidone . Furthermore, the evidence

supporting the efficacy of low-dose thiazide diuretics in the management of
hypertension comes primarily from trials using chlorthalidone, such as ALLHAT
[13] . There is little if any evidence that hydrochlorothiazide alone in a dose of
12.5 to 25 mg/day reduces cardiovascular events [ 24-26] and the blood
pressure may not be as well-controlled overnight [ 17,27] . In addition, in the
ACCOMPLISH trial, which compared combination therapy with benazepril plus
either hydrochlorothiazide (12.5 to 25 mg/day) or amlodipine , cardiovascular
outcomes were worse in the benazepril-hydrochlorothiazide group. (See
"ACCOMPLISH trial" below ).
Choice of thiazide diuretic Based on the above observations, we and
other experts suggest that chlorthalidone (12.5 to 25 mg/day) is the low-dose
thiazide diuretic of choice [ 18,24-26 ] . However, the choice may vary with the
clinical setting:
In most patients not previously treated with a thiazide diuretic, we
suggest low-dose chlorthalidone, rather than
hydrochlorothiazide .
However, among frail older patients who are less than 10 mmHg above
goal blood pressure, some consider low-dose hydrochlorothiazide a
reasonable alternative.
Among patients already treated with low-dose hydrochlorothiazide, the
optimal approach has not been defined. Some experts would switch all
patients to chlorthalidone at their next visit, with the possible exception
of those who monitor their blood pressure at home and have values
below goal on the first morning measurement.
Monitoring for hypokalemia Chlorthalidone produced hypokalemia
requiring therapy in 7 to 8 percent of patients in large clinical trials including
ALLHAT and SHEP [ 13,21] . It is possible that hypokalemia is more common
with chlorthalidone than hydrochlorothiazide , given its longer duration of
action. Concurrent use of a low salt diet will both contribute to blood pressure
lowering and reduce the risk of hypokalemia [ 28,29] . (See "Diuretic-induced
hypokalemia" ).
Monitoring for the development of hypokalemia is warranted with all thiazide
diuretics. In stable patients on a fixed dose of either
chlorthalidone or
hydrochlorothiazide , potassium loss, like other diuretic-induced fluid and
electrolyte complications, occurs only during the first two weeks of therapy
before a new steady state is established ( show figure 8 ). Thus, a stable
patient with a normal serum potassium concentration at three weeks is not at
risk of late hypokalemia unless the diuretic dose is increased, extrarenal
potassium losses increase, or dietary potassium intake is reduced. ( See "The
steady state" and see "Time course of diuretic-induced electrolyte
complications" ).

Issues with chlorthalidone We recognize that most clinicians,

particularly in the United States, have limited, if any, experience with
chlorthalidone . The basic principles of monitoring for hypokalemia with
chlorthalidone are identical to those with hydrochlorothiazide , as described in
the preceding section.
There are three other potential limitations:
It is not available in all formularies and pharmacies.
There is no 12.5 mg tablet. Thus, 25 mg tablets of generic
chlorthalidone need to be cut in half. There is a more expensive 15 mg
brand name preparation (Thalitone). This preparation has greater
bioavailability than generic chlorthalidone, and clinical studies suggest
that its antihypertensive efficacy is closer to 25 mg of generic
chlorthalidone.
In patients who require combination therapy, the current lack of
availability (compared to hydrochlorothiazide ) of fixed dose combination
pills with ACE inhibitors, angiotensin II receptor blockers, and
long-acting calcium channel blockers. ( See "Combination therapy"
below See "Combination therapy" below ).
ACCOMPLISH trial Only one major trial, ACCOMPLISH, directly compared
different combination regimens in hypertensive patients who require two
drugs [ 30] . The results of ACCOMPLISH are discussed in detail elsewhere but
will be briefly reviewed here. ( See "Choice of therapy in essential
hypertension: Clinical trials" , section on ACCOMPLISH trial).
The ACCOMPLISH trial included 11,506 patients with hypertension who were
at high risk for a cardiovascular event and, despite prior antihypertensive
therapy in 97 percent (most requiring two or more drugs), had a mean
baseline blood pressure of 145/80 mmHg [ 31] . The patients were randomly
assigned to initial combination therapy with benazepril (20 mg/day) plus
either amlodipine (5 mg/day) or hydrochlorothiazide (12.5 mg/day). Benazepril
was increased to 40 mg/day in both groups at one month. If goal blood
pressure was not attained, the amlodipine dose was increased to 10 mg/day
and the hydrochlorothiazide dose to 25 mg/day.
The primary end point was measured as the time to the first event, which was
a composite of death from cardiovascular causes, nonfatal myocardial
infarction, nonfatal stroke, hospitalization for angina, resuscitation after
sudden cardiac death and coronary revascularization. The trial was terminated
early by the Data Safety Monitoring Board at a mean follow-up of 36 months
when the prespecified stopping rule was exceeded.

The primary end point was achieved significantly less often in the
benazepril-amlodipine group (9.6 versus 11.8 percent, hazard ratio 0.80, 95%
CI 0.72-0.90). There was a similar reduction in the secondary end point of
cardiovascular death or nonfatal myocardial infarction or stroke (5.0 versus
6.3 percent, hazard ratio 0.79). These benefits increased progressively over
the duration of the trial ( show figure 9 ).
The mean office blood pressure was slightly (about 1 mmHg) but significantly
lower in the benazepril-amlodipine group (131.6/73.3 compared to 132.5/74.4
mmHg). However, in contrast to all other major randomized trials that
compared the outcomes with different antihypertensive drugs, ACCOMPLISH
included 24-hour blood pressure monitoring in a subset of 573 patients. The
results were presented at the American Society of Hypertension meeting in
May 2009. The 24-hour average blood pressure was nonsignificantly higher
(1.6/0.3 mmHg) in the benazepril-amlodipine group. Similar trends were noted
with daytime and nighttime average blood pressures.
Thus, the clinical benefits with the benazepril-amlodipine combination cannot
be explained by better blood pressure control. The difference in outcome can
be explained in one or both of two ways: there is a beneficial effect of
benazepril-amlodipine or an adverse effect of benazepril-hydrochlorothiazide .
There is no way to distinguish between these possibilities.
Implications for practice The ACCOMPLISH trial was large, well
designed, and without apparent flaws. In addition, it compared combination
regimens using the three classes of antihypertensive drugs that are preferred
for initial monotherapy in the absence of a specific indication for a particular
drug class. ( See "Initial monotherapy" below and see "Indications for specific
drugs" below ).
Some have suggested that confirmatory trials are required before practice
recommendations are changed. However, such information is unlikely to be
available for many years.
We and our peer reviewers feel that the results of ACCOMPLISH should not be
ignored and that they raise the following questions about the use of a
long-acting ACE inhibitor/ARB and a long-acting dihydropyridine calcium
channel blocker (A/dC):
Is the A/dC combination the preferred regimen in previously untreated
patients who require two drugs because they are more than 20/10
mmHg above goal?
Should patients being treated with the combination of an ACE
inhibitor/ARB and a thiazide diuretic who are at goal and doing well be
switched to A/dC? Approximately 75 percent of patients in ACCOMPLISH
had previously been treated with two or more antihypertensive drugs

[31] .
In patients being treated with and having responded to a thiazide
diuretic who require a second antihypertensive drug, should the
thiazide be discontinued and the patient started on A/dC?
Does ACCOMPLISH affect the choice of monotherapy, with a long-acting
ACE inhibitor/ARB or a long-acting dihydropyridine calcium channel
blocker being preferred so that the second class can be added if the
patient responds but does not reach goal with the initial drug?
These issues will be discussed below. ( See "Combination therapy" below See
"Combination therapy" below and see "Summary and recommendations"
below ).
INITIAL MONOTHERAPY The goal of antihypertensive therapy in most
patients with uncomplicated combined systolic and diastolic hypertension is a
blood pressure of less than 140/90 mmHg. A lower goal blood pressure, less
than 130/80 mmHg, is indicated in patients with diabetes mellitus, proteinuric
chronic kidney disease, and known atherosclerotic cardiovascular disease.
Among patients with isolated systolic hypertension, the goal systolic pressure
is less than 140 mmHg, but the diastolic blood pressure should not be
reduced to less than 65 mmHg in elderly patients to attain the target systolic
pressure. ( See "What is goal blood pressure in treatment of hypertension?"
).
Initial monotherapy is successful in most patients with mild essential
hypertension. However, single drug therapy is unlikely to attain goal blood
pressure in patients whose blood pressures are more than 20/10 mmHg
above goal. In such patients, initial combination therapy using two drugs is
recommended. ( See "First-line combination therapy" below ).
General principles Each of the antihypertensive agents is roughly equally
effective in lowering the blood pressure, producing a good antihypertensive
response in 30 to 50 percent of patients ( show figure 1 and show figure 2 )
[1-5] . There is, however, wide interpatient variability as many patients will
respond well to one drug but not to another. There are some predictable
differences, such as black patients generally responding better to
monotherapy with a thiazide diuretic or calcium channel blocker and relatively
poorly to an ACE inhibitor or beta blocker ( show figure 2 ). (See "Monotherapy
based upon age and race" below ).
In addition to these general observations, the following findings were noted
in a 2009 meta-analysis of randomized trials [ 2] :
Defining the standard dose of a class of drugs as the usual
maintenance dose in reference pharmacopoeias, the largest reduction
in blood pressure was seen at a half standard dose with only modestly

greater reductions in systolic and diastolic blood pressures at standard

or twice standard doses. As examples, the average fall in systolic blood
pressure over 24 hours with half standard, standard, and twice
standard doses was 7.1, 9.1, and 10.9 mmHg with data from all classes
combined and 7.4, 8.8, and 10.3 mmHg with a thiazide diuretic. ( See
"Drug dosing and drug frequency" below ).
With thiazide diuretics, calcium channel blockers, and beta blockers, the
rate of symptomatic and metabolic adverse effects increased
significantly with standard or twice standard doses compared to half
standard doses. Similar findings have been noted in other studies
(show figure 7 ). In contrast, there was a very low rate of side effects
with ACE inhibitors and ARBs with no dose dependence.
Thus, after the initial dose, going to higher doses produced on average
relatively small further reductions in blood pressure at the price of an
increasing rate of adverse effects. As a result, we generally limit dose titration
to one step with a given antihypertensive drug (eg, 12.5 to 25 mg of
chlorthalidone and 5 to 10 mg of amlodipine ).
These observations suggest that two or even three drugs at half standard
doses might have greater antihypertensive efficacy and less toxicity than one
drug at standard or twice standard doses and might produce better patient
outcomes [ 2] . Randomized trials to validate this hypothesis have not been
performed.
Choice of drug Some patients have an indication for a specific drug or
drugs that is unrelated to essential hypertension (eg, a nondihydropyridine
calcium channel blocker or beta blocker for rate control in patients with atrial
fibrillation). (See "Indications for specific drugs" below ).
In the absence of a specific indication, there are three main classes of drugs
that have been used for initial monotherapy: thiazide diuretics, long-acting
calcium channel blockers (most often a dihydropyridine), and ACE inhibitors or
angiotensin II receptor blockers (ARBs). Each of these classes of drugs have
been equally effective in monotherapy trials if the attained blood pressure is
similar. Beta blockers are NOT commonly used for initial monotherapy in the
absence of a specific indication, since they may have an adverse effect on
some cardiovascular outcomes, particularly in older patients. ( See "Indications
for specific drugs" below and see "Importance of attained blood pressure"
above and see "Beta blockers" below ).
Among patients in whom there is a reasonable likelihood of requiring a second
drug (eg, more than 10/5 mmHg above goal), some physicians who practice
according to the results of the ACCOMPLISH trial prefer initial therapy with a
long-acting ACE inhibitor/ARB or a long-acting dihydropyridine calcium channel

blocker, since the second class can be added if additional therapy is required
to achieve the desired combination regimen. As described in the next section,
the choice between these drug classes may be influenced by age and race.
(See "ACCOMPLISH trial" above ).
This is a change from the current practice of many physicians. Low-dose
hydrochlorothiazide (12.5 to a maximum of 25 mg/day) is widely used and,
after publication of the ALLHAT trial, was recommended as initial monotherapy
in most patients with mild essential hypertension by JNC 7 and others [ 14,15]
. However, hydrochlorothiazide appears to be less effective and has a shorter
duration of action than chlorthalidone , and there is little, if any, evidence that
low-dose hydrochlorothiazide alone reduces cardiovascular events as
opposed to the evidence with chlorthalidone. ( See "Chlorthalidone versus
hydrochlorothiazide" above ).
Thus, when a thiazide diuretic is used, we and others suggest
chlorthalidone
(12.5 to a maximum of 25 mg/day) [24,25] , which produced the best
outcomes in ALLHAT, not hydrochlorothiazide at the same doses.
Chlorthalidone is probably associated with somewhat greater risks of
hypokalemia, glucose intolerance, and new onset diabetes mellitus than
hydrochlorothiazide [ 32] .
Monotherapy based upon age and race The likelihood of a good
response is increased when two simple clinical characteristics, age and race,
are utilized to determine drug treatment. The following patients respond best
to different types of antihypertensive agents used as monotherapy [
33,34] :
Younger patients respond best to angiotensin converting enzyme (ACE)
inhibitors or angiotensin-II receptor blockers (ARBs) and beta blockers.
However, beta blockers are not commonly used for initial monotherapy
in the absence of a specific indication because of a possible increase in
cardiovascular events, particularly in older patients. ( See "Beta
blockers" below ).
Support for this differential antihypertensive response in younger patients is
supported by a study of 56 young (22 to 51 years) white hypertensive
patients who were treated in a crossover rotation with the four main classes
of antihypertensive drugs: ACE inhibitor, thiazide diuretic, long-acting
dihydropyridine CCB, and beta blocker [ 33] . Significantly greater responses in
both systolic and diastolic blood pressure levels were noted with the ACE
inhibitor and beta blocker than with the CCB or diuretic.
Black patients ( show figure 2 ) and elderly patients often respond best
to a thiazide diuretic or long-acting calcium channel blocker [ 5,31] .
These different responses may be at least partially related to the
baseline plasma renin activity (PRA) [ 35] . Older and black

hypertensives usually have lower PRA values than younger and white
patients. However, many elderly hypertensive patients have a specific
indication for an ACE inhibitor or ARB, including heart failure, prior
myocardial infarction, and proteinuric chronic kidney disease. ( See
"Treatment of hypertension in blacks" and see "Treatment of
hypertension in the elderly, particularly isolated systolic hypertension"
and see "Indications for specific drugs" below ).
Sequential monotherapy Each of the recommended first-line agents will
normalize the BP in 30 to 50 percent of patients with mild hypertension ( show
figure 1 and show figure 2 ) [1-5] . A patient who is relatively unresponsive to
one drug has an almost 50 percent likelihood of becoming normotensive on a
second drug [ 36] . Thus, in a patient who has little or no fall in BP after an
adequate dose of drug 1, switching to (rather than adding) drug 2 and, if this
is ineffective, switching to drug 3 may allow as many as 60 to 80 percent of
patients with mild hypertension to initially be controlled with a single agent
[33,36] .
There are no strict guidelines as to how to perform sequential monotherapy.
As the dose is increased with most antihypertensive drugs, the
antihypertensive response attenuates and side effects become more
prominent with the relative exception of ACE inhibitors and ARBs in patients
with normal renal function ( show figure 10 ) [37] . As a result, we generally
limit dose titration to one step with a given drug (eg, 12.5 to 25 mg of
chlorthalidone and 5 to 10 mg of amlodipine ). Using higher doses may produce
a lesser blood pressure response and more toxicity than switching to an initial
dose of a second drug. ( See "General principles" above ).
This regimen of trying to find the one drug to which the patient is most
responsive may minimize side effects, maximize patient compliance, and is as
effective as some forms of combination therapy. However, over time, more
than one drug will be needed in many patients who are initially controlled. In
ALLHAT, for example, the proportion of patients treated with more than one
drug increased from 26 to 33 percent at one year to 40 to 43 percent at five
years [ 13] . (See "Addition of a second drug" below ).
Drug dosing and drug frequency Although stepped care therapy has
emphasized pushing initial therapy, as necessary, to the maximum
recommended dose, the steepest part of the dose-response curve is typically
seen at lower doses: good responders generally respond to low doses with
few side effects, while higher doses produce more side effects often with little
further reduction in blood pressure ( show figure 10 ) [2,38] . (See "General
principles" above ).
As examples, patients often respond as well to 12.5 or 25 mg of
hydrochlorothiazide (or its equivalent) per day as they do to 50 mg ( show

figure 6 ), to 50 mg of atenolol as they do to 100 mg, to 100 mg of captopril as

they do to 450 mg, to 10 to 15 mg of enalapril as they do to 20 or 40 mg, and
to 50 mg of losartan as they do to 100 mg [ 19,39-43 ] . In addition to its
efficacy, low-dose hydrochlorothiazide is less likely to produce the metabolic
abnormalities that are often seen at higher doses ( show figure 7 ) [19] . (See
"Thiazide diuretics in essential hypertension" ).
The issue of dose frequency relates to the possible absence of 24-hour
efficacy with shorter-acting drugs [ 44-46] . Once daily dosing with such drugs
gives a greater peak response, but the BP tends to return toward baseline in
the early morning hours, well before the next dose. This is a potential
concern, since a greater daily BP load and early morning abrupt elevations in
BP can increase cardiovascular risk. Giving one-half the dose twice a day
produces a lesser peak effect but a more sustained response; however,
patient compliance may be reduced [ 46,47] . (See "Ambulatory blood pressure
monitoring and white coat hypertension in adults" , section on Influence on
therapy of hypertension).
Thus, drugs that are longer acting are preferred [ 48] . It is prudent to check
the BP in the morning prior to the next dose whenever a once daily regimen is
used [ 49] .
Indications for specific drugs The general recommendations for initial
therapy should be amended in patients with specific underlying conditions in
whom specific agents might offer particular benefit independent of blood
pressure control ( show table 1 ) [6,14,50] . These indications include the
demonstration that ACE inhibitors improve outcomes in a number of high risk
settings and that beta blockers improve survival in patients with systolic heart
failure or a prior myocardial infarction [ 6] . (See "Indications for use of and
contraindications to specific antihypertensive drugs" and topics on the specific
disorders).
ACE inhibitors ACE inhibitors are first-line therapy in all patients who
have HF or asymptomatic LV dysfunction, in all patients who have had an ST
elevation MI, in patients with a non-ST elevation MI who have had an anterior
infarct, diabetes, or systolic dysfunction, and in patients with proteinuric
chronic kidney disease. ( See "ACE inhibitors in heart failure due to systolic
dysfunction: Therapeutic use" and see "Angiotensin II receptor blockers in
heart failure due to systolic dysfunction: Therapeutic use" and see
"Angiotensin converting enzyme inhibitors and receptor blockers in acute
myocardial infarction: Recommendations for use" and see "Antihypertensive
therapy and progression of nondiabetic chronic kidney disease"
).
It has been suggested that ACE inhibitors and ARBs have a cardioprotective
effect independent of blood pressure lowering in patients at high risk for a
cardiovascular event. However, as mentioned above and described in detail

elsewhere, the available evidence suggests that the attained blood pressure,
not the drug used, is of primary importance in such patients. ( See "Importance
of attained blood pressure" above and see "Choice of antihypertensive drug
and blood pressure goal in patients at increased risk for a cardiovascular
event" ).
Angiotensin II receptor blockers The specific indications for and efficacy
of angiotensin II receptor blockers (ARBs) are similar to those with ACE
inhibitors. (See "Angiotensin II receptor blockers in heart failure due to
systolic dysfunction: Therapeutic use" and see "Angiotensin converting
enzyme inhibitors and receptor blockers in acute myocardial infarction:
Recommendations for use" and see "Antihypertensive therapy and
progression of nondiabetic chronic kidney disease" ).
There is at least one setting in which ARBs have specific benefit and in which
similar trials have not been performed with ACE inhibitors: severe
hypertension with ECG evidence of left ventricular hypertrophy in LIFE [ 39] .
An ARB can be used instead of an ACE inhibitor in such patients, although it is
highly likely that an ACE inhibitor is equally effective. We would not switch
such a patient who is already receiving and tolerating an ACE inhibitor to an
ARB.
An ARB is particularly indicated in patients who do not tolerate ACE inhibitors
(mostly because of cough). ( See "Differences between angiotensin converting
enzyme inhibitors and receptor blockers" ).
Thiazide diuretics The preferred thiazide diuretic in patients with
essential hypertension is chlorthalidone (12.5 to 25 mg/day), since major trials
such as ALLHAT have shown benefit with this regimen. There is little, if any,
evidence that hydrochlorothiazide at this dose improves cardiovascular
outcomes. Hydrochlorothiazide is both less potent and shorter acting than
chlorthalidone. ( See "Chlorthalidone versus hydrochlorothiazide" above
and
see "Initial monotherapy" above ).
One problem with low-dose chlorthalidone is that there is no 12.5 mg tablet.
Thus, 25 mg tablets of generic chlorthalidone need to be cut in half. There is a
more expensive 15 mg brand name preparation (Thalitone). This preparation
has greater bioavailability than generic chlorthalidone, and clinical studies
suggest that its antihypertensive efficacy is closer to 25 mg of generic
chlorthalidone [ 51] . Another problem with chlorthalidone compared to
hydrochlorothiazide is the current lack of availability of fixed dose combination
pills with ACE inhibitors, angiotensin II receptor blockers, and long-acting
calcium channel blockers.
Diuretics should also be given for volume control in patients with heart failure
or chronic kidney disease, with or without nephrotic syndrome; these settings
usually require loop diuretics. In addition, an aldosterone antagonist

(spironolactone or eplerenone ) is indicated in selected patients with advanced

HF who have relatively preserved renal function and, in patients with less
severe disease, for the prevention or treatment of hypokalemia. ( See "Use of
diuretics in heart failure" ).
Calcium channel blockers There are no absolute indications for calcium
channel blockers in hypertensive patients. Long-acting dihydropyridines are
most commonly used. Like beta blockers, the non-dihydropyridine calcium
channel blockers ( verapamil , diltiazem ) can be given for rate control in
patients with atrial fibrillation or for control of angina. Calcium channel
blockers also may be preferred in patients with obstructive airways disease.
(See "Treatment of hypertension in asthma and COPD" ).
Beta blockers A beta blocker without intrinsic sympathomimetic activity
should be given after an acute myocardial infarction and to stable patients
with heart failure or asymptomatic left ventricular dysfunction (beginning with
very low doses to minimize the risk and degree of initial worsening of
myocardial function). The use of beta blockers in these settings is in addition
to the recommendations for ACE inhibitors in these disorders. ( See "Beta
blockers in the management of acute coronary syndrome" and see "Use of
beta blockers in heart failure due to systolic dysfunction" ).
Beta blockers are also given for rate control in patients with atrial fibrillation,
for control of angina, and for symptom control in a number of other disorders
(show table 1 ).
In the absence of such indications, we and others suggest that beta blockers
should NOT be used for initial antihypertensive therapy [ 32,52,53 ] ,
particularly in patients over age 60. Compared to other antihypertensive
drugs in the primary treatment of hypertension, beta blockers (not all trials
used atenolol ) may be associated with a higher rate of stroke (particularly
among smokers) [ 54,55] , coronary disease [ 55] , all cardiovascular events
[55] , and perhaps, with atenolol, a small increase in mortality [ 56] . These
effects are primarily seen in patients over age 60 [ 55,57,58 ] . Beta blockers
are also associated with impaired glucose tolerance and an increased risk of
new onset diabetes [ 32] , with the exception of vasodilating beta blockers
such as carvedilol and nebivolol [59,60] .
The data supporting these conclusions are presented separately. (
See
"Choice of therapy in essential hypertension: Clinical trials" , section on Beta
blockers as initial therapy?, and see "Treatment of hypertension in diabetes
mellitus" , section on Beta blockers).
Alpha blockers The ALLHAT trial cited above included a doxazosin arm
that was terminated prematurely because of a significantly increased risk of
heart failure compared to chlorthalidone (relative risk 2.0 after adjusting for a
3 mmHg higher in-trial systolic pressure with doxazosin) noted during an

interim analysis [ 61] and a higher rate of cardiovascular events [ 62] . Thus, an
alpha blocker is not recommended for initial monotherapy, with the possible
exception of older men with symptoms of prostatism, particularly if they are
not at high cardiovascular risk. ( See "Medical treatment of benign prostatic
hyperplasia" ).
COMBINATION THERAPY There are two issues related to combination
therapy: use as first-line therapy; and addition of a second drug when the
goal blood pressure is not achieved with monotherapy. The following
discussion assumes that the patient does not have an indication for the use
of specific drugs. ( See "Indications for specific drugs" above ).
Recommendations for combination therapy were made in the 2003 JNC 7
report, the 2004 British Hypertension Society guidelines, and the 2007
European Societies of Hypertension and Cardiology guidelines [ 14,34,63 ] .
However, the guidelines were published well before the ACCOMPLISH trial,
which we feel provides the best evidence for combination therapy.
First-line combination therapy Administering two drugs as initial therapy
should be considered when the blood pressure is more than 20/10 mmHg
above goal, as recommended in the JNC 7 report [ 14] . This strategy may
increase the likelihood that target blood pressures are achieved in a
reasonable time period. Fixed-dose combination preparations are available
that may improve patient compliance and, if both drugs are given at lower
doses, reduce side effects [ 2,37,64,65 ] .
Supine and standing pressures should be measured prior to the initiation of
combination therapy in patients at increased risk for orthostatic (postural)
hypotension, such as elderly patients and those with diabetes. Orthostatic
hypotension is diagnosed when, within two to five minutes of quiet standing,
one or more of the following is present:
At least a 20 mmHg fall in systolic pressure
At least a 10 mmHg fall in diastolic pressure
Symptoms of cerebral hypoperfusion, such as dizziness
(See "Mechanisms and causes of orthostatic and postprandial hypotension"

).

Based upon the results of the ACCOMPLISH trial [ 30] , we recommend the use
of a long-acting dihydropyridine calcium channel blocker plus a long-acting ACE
inhibitor/ARB (such as amlodipine plus benazepril as used in ACCOMPLISH). In
addition, in patients already being treated with and doing well on the
combination of a thiazide diuretic and a long-acting angiotensin inhibitor, we
suggest replacing the thiazide diuretic with a long-acting dihydropyridine
calcium channel blocker. ( See "ACCOMPLISH trial" above ).
Addition of a second drug As noted above, each of the recommended first

line agents will normalize the BP in up to 30 to 50 percent of patients with

mild hypertension [ 5] . In the patient who is relatively unresponsive to one
drug, sequentially trying different agents may allow 60 to 80 percent of
patients with mild hypertension to be initially controlled with a single agent
[33,36] . These issues are discussed in detail above. ( See "Initial
monotherapy" above ).
We generally limit dose titration to one step with a given drug (eg, 12.5 to 25
mg of chlorthalidone or 5 to 10 mg of amlodipine ). Using higher doses
generally produces a lesser blood pressure response and more toxicity than
switching to an initial dose of a second drug ( show figure 10 ) [5,37,66] .
Over time, more than one drug will be needed in many patients who are
initially controlled. In ALLHAT, for example, the proportion of patients treated
with more than one drug increased from 26 to 33 percent at one year to 40 to
43 percent at five years [ 13] .
Based upon the results of the ACCOMPLISH trial [ 30] , we suggest that
combination therapy consist of a long-acting dihydropyridine calcium channel
blocker plus a long-acting ACE inhibitor/ARB (such as amlodipine plus
benazepril ). Thus, if the patient is being treated with one of the drugs, add
the other. In patients being treated with a thiazide diuretic, we suggest
discontinuing the thiazide and starting combination therapy. Approximately 75
percent of patients in ACCOMPLISH had previously been treated with two or
more antihypertensive drugs. ( See "ACCOMPLISH trial" above ).
Beta blockers are now used less often as initial therapy except for patients
with another indication for their use. The preferred second drug in patients
who are treated with a beta blocker are a thiazide diuretic or a
dihydropyridine calcium channel blocker [ 50] . An alpha blocker would be
chosen only if there is another reason for its use, such as symptomatic benign
prostatic hyperplasia.
An ACE inhibitor or ARB is likely to be less effective in patients treated with a
beta blocker, since beta blockers reduce renin secretion and therefore
angiotensin II formation [ 67] , and a beta blocker should be used with caution
in combination with verapamil and to a lesser degree diltiazem . These drugs
can potentiate the cardiac depressant effect of the beta blocker, possibly
leading to or exacerbating bradycardia or heart block.
INFORMATION FOR PATIENTS Educational materials on this topic are
available for patients. ( See "Patient information: High blood pressure in
adults" and see "Patient information: High blood pressure treatment in
adults" and see "Patient information: High blood pressure, diet, and weight" ).
We encourage you to print or e-mail these topic reviews, or to refer patients
to our public web site, www.uptodate.com/patients , which includes these and
other topics.

SUMMARY AND RECOMMENDATIONS The amount of blood pressure

reduction is generally the major determinant of a decrease in cardiovascular
risk in patients with hypertension, not the specific antihypertensive drug(s).
However, this may not apply to combination therapy. In the ACCOMPLISH trial,
amlodipine plus benazepril was associated with a 20 percent lower rate of
cardiovascular events compared to hydrochlorothiazide plus benazepril,
despite slightly higher 24-hour blood pressures in the amlodipine arm. ( See
"Importance of attained blood pressure" above
and see "ACCOMPLISH trial"
above ).
Some hypertensive patients have underlying conditions for which specific
antihypertensive drugs might offer particular benefit independent of blood
pressure control. The following recommendations do not apply to such
patients. ( See "Indications for specific drugs" above ).
Monotherapy Among hypertensive patients without an indication for a
specific drug, the major classes of drugs that have been used for
monotherapy are a low dose thiazide diuretic, long-acting angiotensin
converting enzyme (ACE) inhibitor/angiotensin II receptor blocker (ARBs), or a
long-acting dihydropyridine calcium channel blocker.
Given the preference for an ACE inhibitor/ARB plus a dihydropyridine
calcium channel blocker in patients requiring combination therapy, we
suggest use of one of these drug classes as initial therapy so that the
other can be added, if necessary ( Grade 2C). If this approach is
chosen, an ACE inhibitor/ARB may be more effective in younger patients,
and a dihydropyridine calcium channel blocker may be more effective in
elderly and black patients. ( See "Initial monotherapy" above and see
"Monotherapy based upon age and race" above ).
If a thiazide-type diuretic is chosen, we suggest chlorthalidone rather
than hydrochlorothiazide (Grade 2B). Most clinicians, particularly in the
United States, have limited, if any, experience with chlorthalidone,
which may be somewhat more likely to induce hypokalemia than
hydrochlorothiazide at the same dose. The basic principles of monitoring
for hypokalemia with chlorthalidone are identical to those with
hydrochlorothiazide. ( See "Choice of thiazide diuretic" above and see
"Choice of thiazide diuretic" above and see "Issues with chlorthalidone"
above ).
We recommend that patients who have a minimal or no response to the
initial antihypertensive drug be treated with sequential monotherapy
(Grade 1B). (See "Sequential monotherapy" above ).
Combination therapy

Among patients who have an initial blood pressure more than 20/10
mmHg above goal, we recommend therapy with the combination of a
long-acting ACE inhibitor/ARB plus a long-acting dihydropyridine calcium
channel blocker ( benazepril plus amlodipine was used in the
ACCOMPLISH trial) ( Grade 1B). (See "ACCOMPLISH trial" above and see
"First-line combination therapy" above ).
Among patients who are already being treated with an ACE
inhibitor/ARB plus a thiazide diuretic and have attained goal blood
pressure, we suggest stopping the thiazide and switching to a
long-acting dihydropyridine calcium channel blocker ( Grade 2B). We
suggest continuing therapy in patients who are well controlled on
combinations other than an ACE inhibitor/ARB plus a thiazide ( Grade
2C).
Among patients being treated with a thiazide diuretic as monotherapy
who have responded but have not attained goal blood pressure, we
suggest stopping the thiazide and switching to a long-acting ACE
inhibitor/ARB plus a long-acting dihydropyridine calcium channel blocker
(Grade 2B).
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GRAPHICS

Antihypertensive response to different drugs in whites

Response rates to single drug therapy for hypertension in whites under

the age of 60. There were no significant differences in response,
except that hydrochlorothiazide (HCTZ) appeared to be least
effective. A response was defined as a diastolic pressure below 90
mmHg at the end of the titration phase and below 95 mmHg at one
year. The pattern of response was similar but the success rate for
each drug was reduced by five to 15 percent if goal diastolic pressure
were less than 90 mmHg at one year. There were between 30 and 39
patients in each group. Data from Materson, BJ, Reda, DJ, Cushman,
WC, et al, N Engl J Med 1993; 328:914. Correction and additional data:
Am J Hypertens 1995; 8:189.

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