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Vol. 161 No. 6, March 26, 2001 |
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Original Investigation |
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Adverse Drug Effects, Compliance, and Initial Doses of Antihypertensive Drugs Recommended by the Joint National Committee vs the Physicians' Desk Reference
Jay S. Cohen, MD
Arch Intern Med. 2001;161:880-885.
ABSTRACT
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Background Compliance problems are common causes of the inadequate treatment of
hypertension, with 16% to 50% of patients quitting treatment within 1 year.
Dose-related adverse drug events (ADEs) frequently cause compliance problems,
and many ADEs occur with the initial doses of antihypertensive drugs. Thus,
it is an established tenet to initiate antihypertensive therapy at low doses
to avoid ADEs that diminish patients' quality of life and reduce compliance.
However, what are the lowest effective doses of antihypertensive drugs?
Objective To compare the initial doses recommended in the Physicians' Desk Reference (PDR) with
those recommended by the Sixth Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High
Blood Pressure (JNC VI).
Methods Review of the latest JNC VI report (1997) and the 1999 and 2000 editions
of the PDR and the medical literature.
Results The JNC VI recommends substantially lower initial doses for 23 (58%)
of 40 drugs, compared with the PDR. In addition,
for 37 (82%) of 45 drugs, PDR guidelines do not suggest
lower initial doses for old or frail patients than for younger adults.
Conclusions Although the PDR is the drug reference most
used by physicians, it does not reflect the lowest initial doses that are
recommended by the JNC VI for many of the most prescribed antihypertensive
drugs. Because avoidance of ADEs is essential to maintaining compliance with
antihypertensive therapy, and because many antihypertensive ADEs are dose
related, physicians must know the very lowest, effective, least ADE-prone
doses. Patients and physicians would benefit by establishing mechanisms to
make this information readily available to all practicing physicians.
INTRODUCTION
DURING THE past quarter century, the medical profession has made a major
effort to improve awareness among people who have hypertension and to start
their treatment.1 The result has been a significant
reduction in the long-term sequelae of hypertension, including myocardial
infarctions and cerebrovascular accidents. However, during the 1990s, improvements
in these measures slowed,2-3 and
only 29% of the 50 million Americans with hypertension had attained a blood
pressure below 140/90 mm Hg.4-5
Therefore, efforts continue to be directed at (1) reaching unaware or untreated
hypertensive persons and facilitating treatment; (2) improving the percentage
of patients achieving treatment goals by optimizing therapeutics; and (3)
improving compliance by reducing the percentage of patients quitting treatment.
Optimizing therapeutics and improving compliance are the focus of this article.
COMPLIANCE WITH ANTIHYPERTENSIVE TREATMENT
Compliance may be defined as the extent to
which a patient's behavior conforms to medical advice.6
Long-term compliance with antihypertensive medication regimens has been poor.
In one study, only 49% of patients took more than 80% of their prescribed
dosages during the first year of treatment.7
Other studies indicate that 16% to 50% of hypertensive patients quit taking
their medications within the first year of treatment.7-10
These numbers improve considerably once patients have become established
in treatment regimens. A survey of 79 000 hypertensive patients in Saskatchewan
found a dropout rate among new patients of 22% in the first year and 54% after
4.5 years, leaving a persistence rate that the authors deemed "remarkably
poor."11 Although patients with newly diagnosed
hypertension frequently quit treatment, the authors noted that "patients who
have successfully initiated antihypertensive treatment tend to remain in treatment."
Thus, the successful initiation of treatment itself is a goal, particularly
in terms of ensuring the continuation of treatment. The authors underscored
this point: "Our analyses emphasize the importance of maximizing the likelihood
of successful early treatment of hypertension and thus increasing the proportion
of patients taking medication over the long term."11
ADVERSE DRUG EVENTS AND COMPLIANCE
There are many factors that affect compliance, such as the cost of medications
and the inadequacy of physicians' explanations to patients of the importance
of treating hypertension, which often is asymptomatic. A primary reason for
poor compliance among patients receiving antihypertensive medications is adverse
drug events (ADEs), many of which are dose related.12-14
In one study, 34% of patients reported unacceptable ADEs.15
Because of the high incidence of ADEs, physicians must consider quality-of-life
issues in selecting antihypertensive drugs and doses. One difficulty is that
many antihypertensive medications cause ADEs at therapeutic doses. Although
physicians may consider ADEs such as dizziness, headaches, constipation, low
energy, or sedation as minor, these can greatly interfere with normal functioning,
which many patients find unacceptable. Not infrequently, sexual functioning
is impaired, another difficult ADE for patients to accept.
These problems are compounded by the nature of hypertension, which may
cause few symptoms. Treatment that provokes an ADE may make some patients
feel subjectively worse than before treatment initiation. Patients who believe
that they must choose between a comfortable but shortened life vs an ADE-afflicted
but prolonged life often choose the former. Because compliance is intimately
related to the avoidance of troublesome ADEs, physicians are advised to start
antihypertensive therapy at the very lowest effective drug dosages. However,
what are the lowest effective doses of antihypertensive drugs? And are the
data on the lowest effective doses readily available to physicians? This analysis
attempts to answer these questions.
MATERIALS AND METHODS
The Physicians' Desk Reference (PDR)16-17 was selected
because it contains the dosages that are recommended by the drugs' manufacturers
and approved by the Food and Drug Administration, and the dosage recommendations
of other drug references are usually very similar to those of the PDR. The PDR is the drug reference used most
often among physicians18-20;
approximately 90% of physicians rely on the PDR for
dosage information.18 It is also used extensively
by consumers, who purchase half a million copies annually. The 1999 and 2000
editions were consulted for this analysis.
The Sixth Report of the Joint National Committee on the Detection, Evaluation,
and Treatment of High Blood Pressure (JNC VI)1
was selected because the JNC is a respected panel of experts on hypertension
that issues regular reports on the status of antihypertensive therapy in America.
The JNC VI, the most recent report, was published in 1997 and contains a comprehensive
list of antihypertensive drugs with the panel's recommended dosages. These
dosages were compared with the dosage recommendations in the PDR.
RESULTS
The JNC VI lists 57 antihypertensive drugs, but 12 are no longer listed
in the 1999 or 2000 PDR or are listed only briefly
without dosage guidelines. Another 5 drugs (guanfacine hydrochloride, nifedipine,
prazosin hydrochloride, terazosin hydrochloride, and valsartan) are not produced
in a form that would allow the use of lower dosages. Of the remaining 40 drugs,
the JNC VI recommended initial doses for 23 (58%) that were substantially
lower than those recommended by the PDR (Table 1). All 23 dose disparities occurred
among the 34 drugs (68%) in 5 frequently prescribed groups: angiotensin-converting
enzyme inhibitors, angiotensin II receptor blockers, ß-blockers, calcium
antagonists, and diuretics. Except for chlorthalidone and one brand of metoprolol
succinate, the PDR initial doses were at least 100%
higher than the JNC VI doses. These disparities occurred with some of the
most prescribed antihypertensive drugs, such as amlodipine besylate, atenolol,
bisoprolol fumarate, diltiazem hydrochloride, lisinopril, losartan potassium,
metoprolol, propranolol hydrochloride, and ramipril.21
There were no drugs for which the PDR recommended
lower initial doses than JNC VI. Regarding older patients, for whom experts
often recommend lower initial doses than for younger adults, the PDR guidelines recommended lower doses with only 8 (18%) of 45 drugs
(Table 2).
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Table 1. Differing Recommendations for the Initial Doses of 23 Antihypertensive
Drugs*
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Table 2. Antihypertensive Drugs for Which the PDR Does Not Recommend
Lower Initial Doses for Older Patients*
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Even when the JNC VI and PDR agree on the initial
doses of 17 drugs, even lower doses of these drugs might be effective. For
example, the American Hospital Formulary Service recommends an initial enalapril
dose of 2.5 mg vs 5 mg by JNC VI and the PDR.22 The American Hospital Formulary Service also recommends
0.05 mg of clonidine hydrochloride twice daily initially for some patients
vs 0.1 mg twice daily by the JNC VI and the PDR.
The range of manufactured doses varies considerably among antihypertensive
drugs. Some drugs are produced with 16- or 20-fold dosage ranges (eg, doxazosin
mesylate dosage range, 1-16 mg/d), whereas others are produced with 2- or
3-fold ranges (Table 3). The most
common dosage ranges are 4- and 8-fold. Individual variation in drug response
due to differences in age, weight, sex, ethnic background, state of health,
concomitant medication use, and genetic polymorphisms in drug metabolism is
a long-accepted pharmacological principle. Therefore, drugs offering wider
ranges of dosages that allow maximum flexibility in titrating treatment may
be generally preferable.
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Table 3. Range of Dosages Provided by the Manufacturers of 45 Commonly
Prescribed Antihypertensive Drugs
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COMMENT
THERAPEUTIC GOALS DURING THE INITIAL PHASE OF THERAPY
Because of the importance of avoiding ADEs at the beginning of treatment,
the JNC VI cautions physicians against trying to bring mild-to-moderate hypertension
under control too quickly: "Therapy for most patients (uncomplicated hypertension,
stages 1 and 2) should begin with the lowest dosage . . . to prevent adverse
effects of too great or too abrupt a reduction in blood pressure."1 Other authorities agree.23-24
Sorrentino23 states aptly, "Unless acute target
organ involvement is already present, there are no compelling reasons to lower
blood pressure quickly."
Thus, initial interventions are usually aimed at lifestyle modifications
such as weight loss, stress reduction, exercise, dietary changes, reduction
of alcohol use, and cessation of smoking. Medication interventions are usually
considered secondary, because lifestyle changes alone represent major interventions
and adjustments for many patients and can have substantial impact on blood
pressure.25-27
Because more than 75% of all ADEs are dose related,28-29
starting with the lowest effective doses that minimize ADEs is recommended.
MacConnachie and Maclean12 link compliance
directly to dosage: "Therefore, any measure [that] reduces the dosage requirement
of an antihypertensive while maintaining therapeutic efficacy, or otherwise
limits the possibility of commonly encountered ADEs, will encourage good patient
compliance and so improve long-term control of hypertension." For these reasons,
some physicians subscribe to starting with a dose that may be subtherapeutic
rather than a dose that is "correct" but may provoke troublesome ADEs.
FIRST-DOSE REACTIONS
First-dose reactions are ADEs that occur with the initial dose of a
drug or when the dosage is increased. First-dose reactions have been described
with the use of  -receptor blockers,16
calcium channel blockers,16 ACE inhibitors,30-31 and ß-blockers,32
but clinical experience suggests that first-dose reactions may occur with
any antihypertensive drug. First-dose reactions due to antihypertensive drugs
are frequently dose related and may result from an abrupt lowering of blood
pressure, causing postural hypotension, dizziness, syncope, headaches, lethargy,
or other symptoms. First-dose reactivity explains why a large proportion of
ADEs due to antihypertensive drugs occur at the beginning of treatment9 and may indicate that some patients are sensitive
to the pharmacological effects of the standard initial doses of antihypertensive
drugs that physicians are prescribing.
INITIAL DOSES FOR OLDER PATIENTS
Hypertension is most prevalent among people older than 60 years,1, 33-34 and treatment can
be especially challenging because of altered pharmacokinetics (eg, reduced
liver and kidney function, and increased receptor sensitivity), which can
produce even greater extremes in individual drug response than in younger
adults.35-36 In addition, treatment
is further complicated because two thirds of people older than 65 years take
at least 1 medication daily, with the average being 3 prescription and/or
nonprescription drugs daily.29, 37-38
Thus, the overall incidence of ADEs is 2 to 3 times greater in elderly than
in young adults. These ADEs in older patients are typically dose related38-39 and are the leading cause of older
patients' discontinuing antihypertensive therapy.9
For these reasons, some experts recommend that older patients, especially
those who are frail, ill, or taking other medications, should be prescribed
initial doses that are lower than those for younger adults.29, 36, 38-39
However, 37 (82%) of the 45 antihypertensive drugs examined herein are not
recommended at a lower dose for seniors by the PDR
(Table 3). Some of these are drugs
for which the JNC VI recommends lower initial doses not only for seniors,
but for all patients. Moreover, the pharmacokinetic data of some drugs suggest
the appropriateness of lower doses for seniors. For example, the plasma levels
of acebutolol and bisoprolol are doubled in seniors compared with young adults,16 yet the PDR-recommended
initial doses are the same. With other drugs (eg, nifedipine and diltiazem),
the PDR lacks pharmacological data on the response
of older patients, so the physician's ability to make educated judgments about
dosage is limited. With some drugs, physicians wanting to use half doses are
stymied because the pills do not facilitate this (capsules or irregular or
coated tablets).
RECOMMENDATIONS FOR CLINICAL PRACTICE
Hypertension is the most common indication for visits to US physicians,40 and it is a leading cardiovascular risk factor.11, 41 Because of considerable variation
among patients, the optimal pharmacological treatment of hypertension requires
a flexible approach.42 Such flexibility involves
the use of the lowest effective initial doses to facilitate a positive therapeutic
alliance and to avoid ADEs that may affect compliance. Low-dose therapy allows
patients time to adjust psychologically to the fact they have hypertension
and to begin making lifestyle changes recommended by the physician—no
small undertaking for most patients. Some patients experience distress about
having hypertension and possibly requiring lifelong drug therapy, and they
develop anxiety symptoms that may be mistaken for ADEs, which may lead to
skipping doses or quitting treatment. Drug therapy commencing with minimal
doses is generally more acceptable to patients, allays fears about unpleasant
side effects, and minimizes possible confusion between drug-related ADEs vs
anxiety-related symptoms or coincidental factors.
The danger in commencing treatment with the lowest recommended doses
is, of course, undermedication, which also is a problem in antihypertensive
management today.1 However, undermedication
is usually a result of inadequate follow-up rather than a low initial dose.
The stepwise approach to treating hypertension presupposes that proper titration
will lead to higher doses in some patients or to the addition of 1 or 2 more
antihypertensive drugs, when necessary. The "start low, go slow" approach,
which is intended to minimize dose-related ADEs that hinder compliance, is
effective if proper follow-up and dosage titration are provided.
Some patients experience first-dose reactions when their dosages are
increased. This may sometimes occur because the recommended dosage range is
too narrow or a 100% increase in dosage exceeds the patient's tolerance. Smaller
dosage increases, which may require splitting pills, may sometimes prevent
this complication. Drugs produced as scored pills in wide ranges of doses
provide the most dosage flexibility.
THE NEED FOR A SOURCE OF CURRENT, COMPREHENSIVE, AND READILY AVAILABLE
INFORMATION
Overall, optimal antihypertensive pharmacotherapy in mild-to-moderate
hypertension is most often accomplished when initiated at the lowest effective
doses, to maximize compliance by minimizing ADEs. To provide optimal therapy,
physicians must have a readily available source of current information that
defines the very lowest effective doses of antihypertensive drugs. The PDR, which was initiated 54 years ago as a promotional
device, is now the leading source of drug information among physicians, mainly
because of its easy-to-use format and excellent indexes, and because it is
distributed free to physicians each year.
However, the information in the PDR consists
mainly of the limited prerelease data that the manufacturer and the Food and
Drug Administration deemed necessary for the safe and effective use of medications
at the time of their approvals. This information may not be adequate for making
therapeutic decisions in the much wider range of patients seen in clinical
practice compared with patients undergoing evaluation in prerelease studies.
Ray et al43 have stated: "Although these studies
generally ensure that a drug is efficacious and does not cause unacceptable
harm, pre-marketing studies often fail to provide much of the information
needed to make therapeutic decisions." However, there is no requirement and
little incentive for manufacturers to update the PDR
information regularly to reflect postrelease studies or reports. Thus, the
point of this article is not that the producers of the PDR are failing to fulfill an expected responsibility, but rather that
a situation has developed in which there is no readily available source where
physicians can obtain current information about the best methods of initiating
antihypertensive drug therapy.
This situation requires solutions. Because of the wide popularity of
the PDR, the ideal solution might be to establish
mechanisms by which the information in the PDR can
be kept current to reflect the evolving standards of care and the full range
of proven effective drug dosages. If such mechanisms cannot be established,
then perhaps the free dissemination of the PDR should
be discouraged, and an alternative, objective source of accurate, current
information should be created in its place.
UNANSWERED QUESTIONS
The findings of this article raise many questions. What initial doses
of antihypertensive drugs are physicians actually prescribing? Studies have
shown that the recommendations of the JNC VI have had little impact on the
types of antihypertensive drugs that physicians prescribe,44-45
but this has not been examined in regard to doses. Furthermore, the implementation
of optimal pharmacotherapeutic methods ultimately depends on physicians. If
physicians were better informed about the JNC VI– recommended initial
doses of antihypertensive drugs, would they alter their methods? What would
best motivate them to do so? What would motivate drug manufacturers to define
the lowest, safest doses of new drugs in their prerelease research, to provide
pills that allow for flexible dosing, to provide rational guidelines for older
patients, and to reverse the trend that seems apparent in drug advertising
toward 1-size-fits-all and other simplistic methods of dosing?
With a perennial high incidence of ADEs, most of which are dose related,
and with well-defined problems with ADEs and compliance in treating hypertensive
patients, these questions need to be answered and solutions need to be found
and implemented.
CONCLUSIONS
The optimal pharmacotherapy of hypertension depends on the availability
of information on the full range of effective dosages of antihypertensive
drugs. This includes effective dosages that may be lower than those recommended
by drug manufacturers. The PDR is the most used source
of drug information among physicians, and it is heavily relied on by hospital
staff who may lack the clinical experience to know that PDR dosage recommendations are general guidelines based on limited
prerelease research, not on hard and fast rules of optimal therapeutics. This
analysis reveals that, compared with the PDR, the
initial doses of antihypertensive drugs recommended by JNC VI are substantially
lower for 23 (58%) of 40 drugs for which the use of lower doses was possible.
Moreover, although experts generally suggest reduced initial doses for older
patients, the PDR does not recommend such reductions
for old or even very old patients with 37 of 45 drugs. If the JNC VI recommendations,
which represent prerelease and postrelease data, are considered the state
of the art, mechanisms need to be implemented by which these recommendations
are incorporated into the PDR and the corresponding
package inserts, where physicians are most likely to see and use them. If
such mechanisms cannot be established for the PDR,
another source of current, readily available drug information should be created
so that physicians' methods will keep pace with evolving standards of optimal
pharmacotherapy for patients with hypertension.
AUTHOR INFORMATION
Accepted for publication September 14, 2000.
Corresponding author: Jay S. Cohen, MD, 2658 Del Mar Heights Rd,
#120, Del Mar, CA 92014 (e-mail: jacohen{at}uscd.edu).
From the Department of Family and Preventive Medicine, University of
California– San Diego, La Jolla.
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