Reprinted from
When and how to use self (home) and ambulatory
blood pressure monitoring
Thomas G. Pickering, MD, DPhil and William B. White, MD,
on behalf of the American Society of Hypertension Writing Group
Vol.2(3) (2008) 119-124
Hypertension in pregnancy
Marshall D. Lindheimer, MD, Sandra J. Taler, MD, and F. Gary Cunningham, MD
Vol.2(6) (2008) 484-494
Combination therapy in hypertension
Alan H. Gradman, MD, Jan N. Basile, MD, Barry L. Carter, PharmD,
and George L. Bakris, MD, on behalf of the American Society of Hypertension Writing Group
Vol.4(1) (2010) 42-50
Management of hypertension in the transplant patient
Matthew R. Weir, MD, and Daniel J. Salzberg, MD
Vol.5(5) (2011) 425-432
Published by Elsevier
Journal of the American Society of Hypertension 2(3) (2008) 119 –124
ASH Position Paper: Home and Ambulatory Blood Pressure Monitoring
When and how to use self (home) and ambulatory blood pressure
Thomas G. Pickering, MD, DPhila and William B. White, MDb,*, on behalf of the American
Society of Hypertension Writing Group
Center for Behavioral Cardiovascular Health, Columbia Presbyterian Medical Center, New York, New York, USA; and
Division of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut School of
Medicine, Farmington, Connecticut, USA
This American Society of Hypertension position paper focuses on the importance of out-of-office blood pressure (BP)
measurement for the clinical management of patients with hypertension and its complications. Studies have supported direct
and independent associations of cardiovascular risk with ambulatory BP and inverse associations with the degree of BP
reduction from day to night. Self-monitoring of the BP (or home BP monitoring) also has advantages in evaluating patients
with hypertension, especially those already on drug treatment, but less is known about its relation to future cardiovascular
events. Data derived from ambulatory BP monitoring (ABPM) allow the identification of high-risk patients, independent from
the BP obtained in the clinic or office setting. While neither ABPM nor self-BP monitoring are mandatory for the routine
diagnosis of hypertension, these modalities can enhance the ability for identification of white-coat and masked hypertension
and evaluate the extent of BP control in patients on drug therapy. © 2008 American Society of Hypertension. All rights
Keywords: Ambulatory blood pressure monitoring; home and self-BP monitoring; out-of-office-blood pressure; ASH position paper.
Statement of the Problem
The accurate measurement of blood pressure (BP) remains the most important technique for evaluating hypertension and its consequences, and there is increasing evidence that the traditional office BP measurement procedure
may yield inadequate or misleading estimates of a patient’s
true BP status. The limitations of office BP measurement
arise from at least four sources: 1) the inherent variability of
BP coupled with the small number of readings that are
typically taken in the doctor’s office, 2) poor technique
(e.g., terminal digit preference, rapid cuff deflation, improper cuff, and bladder size), 3) the white coat effect (the
increase of BP that occurs in the medical care environment),
and 4) the masked effect (a decrease of BP that occurs in the
medical care environment that may lead to under treatment;
in the case of ‘masked’ hypertension, the out-of-office BP is
Conflict of interest: none.
*Corresponding author: William B. White, MD, Pat and Jim
Calhoun Cardiology Center, University of Connecticut Health
Center, 263 Farmington Avenue, Farmington, Connecticut 06030.
Tel: 860-679-2104; fax: 860-679-1250.
E-mail: [email protected]
hypertensive while the resting, in-office BP is normotensive, or substantially lower than the out-of-office BP).
Nearly 70 years ago there were observations made that
office BP can vary by as much as 25 mm Hg between
visits.1 The solution to this dilemma is potentially two-fold:
by improving the office BP technique (e.g., using accurate
validated automated monitors that can take multiple readings), and by using out-of-office monitoring to supplement
the BP values taken in the clinical environment.
Out-of-office monitoring takes two forms at the present
time: self (or home), and ambulatory BP monitoring
(ABPM). While both modalities have been available for 30
years, only now are they finding their way into routine
clinical practice. The use of self-BP monitoring (also referred to as home BP monitoring) as an adjunct to office BP
monitoring has been recommended by several national and
international guidelines for the management of hypertension, including the European Society of Hypertension,2 the
American Society of Hypertension (ASH),3 the American
Heart Association (AHA),4 the British Hypertension Society,5 the European Society of Hypertension,6 the Japanese
Hypertension Society,7 the World Health Organization –
International Society of Hypertension,8 and the Joint Na-
1933-1711/08/$ – see front matter © 2008 American Society of Hypertension. All rights reserved.
T.G. Pickering and W.B. White / Journal of the American Society of Hypertension 2(3) (2008) 119 –124
tional Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure (JNC 7).9 In the USA,
the use of self-BP monitoring is growing rapidly: Gallup
polls suggest that the proportion of patients who report that
they monitor their BP at home increased from 38% in 2000
to 55% in 2005. In contrast, the use of ABPM in clinical
practice remains limited, although exact numbers are not
Techniques of Out-of-Office Monitoring
ABPMs are used only by physicians’ offices. They require preprogramming to take readings at preset intervals
(typically every 15 to 30 minutes) throughout the day and
night. They are reasonably accurate and are lightweight (ⱕ
1 lb). The majority of patients can obtain a full profile of BP
and its variability over 24 hours. The hardware and software
of ABPM devices have changed little during the past decade. Because the costs of ABPM have not been covered
well by third party payers, their use has been limited in
clinical practice. Medicare has granted reimbursement for
ABPM but only for the limited indication of suspected
white coat hypertension with an absence of target organ
damage; in our experience, this payment is typically less
than the true cost of the procedure. Other insurers are
becoming more liberal in reimbursing for ABPM but prior
authorization is the rule rather than the exception.
Self-monitoring (home) BP devices have undergone substantial changes during the past decade. The first generation
were aneroid devices that were hand-held, and required
manual inflation and deflation. These devices are now rarely
used, and have been replaced by automated oscillometric
devices, which take single readings that are displayed on a
liquid crystal display (LCD) screen. The more basic devices
do not have memory or a printer, so patients are required to
keep a written log of their BP readings. The accuracy with
which patients obtain and write down the BP readings has
been found to be questionable.10 The monitors that have
been formally validated have been found to be reasonably
accurate; but many marketed self-monitoring devices have
not been formally tested. As self-BP devices are readily
available for purchase by patients and are inexpensive, their
use has increased rapidly over the past decade. Freestanding
devices, such as those found in pharmacies, may not be
regularly maintained and may not be reliable.
The newest generation of self/home BP monitors have the
same BP measurement technique as older devices but have
increasingly sophisticated electronics. Many have memory
so that they can easily compute the average values of the
BP. Some of them will automatically take three readings at
fixed intervals (e.g., one minute) following one press of a
button. The latest models can be programmed to take readings at preset times, which might include periods of sleep.
With this exception, the ability to record the nighttime
pressure has been the exclusive domain of ambulatory mon-
itors and there is increasing evidence that nighttime pressure
is an independent predictor of cardiovascular risk.11 The
ability of programmable self/home BP monitors could make
nighttime readings more practical, although experience is
limited at present.
The more sophisticated self/home BP monitors are distinctly more expensive than the currently available ones,
and it is not clear whether they will be optimally used. Some
patients will purchase these more expensive devices for self
use but it is also possible that physicians will purchase these
recorders and charge patients a modest fee for a diagnostic
evaluation. This might include a week’s worth of morning
and evening readings plus a number of nighttime readings.
The monitors often have models with different size cuffs –
the inflatable part of the cuff should cover at least 80% of
the circumference of the upper arm. About half of the users
may need a large cuff.
Clinical and Scientific Background
Self and ABPM can provide unique information that may
be of help both for making treatment decisions and for
evaluating the response to treatment (Table). The mainstay
for the justification of both procedures is that there is
steadily increasing and substantial evidence that both measures give a better prediction of risk than office BP. This has
been shown in numerous studies using ambulatory BP measurements,11–18 and in several studies using self-monitoring
of the BP.18 –21 In general, when there is a discrepancy
between the office BP and the out-of-office BP, the risk
follows the latter more closely. Thus, patients with white
coat hypertension (high office BP and normal out-of-office
BP) are at relatively low risk,17 while patients whose outof-office BP is higher than anticipated from the office BP
are at relatively high risk.15 This latter condition has been
referred to as masked, or hidden hypertension, on the
grounds that it is not normally detected by conventional
office BP measurements.22 Even in treated hypertensive
patients, a high out-of-office BP is a marker for increased
Attributable to its inherent variability, using a small number of readings yields poor reproducibility for the BP level.
By increasing the number of readings used to calculate the
average, both self and 24-hour ambulatory monitoring give
much better estimates of the average. In one study,23 home
BP was the most reproducible (lowest standard deviation of
the differences between sets of measurements: 6.9/4.7 mm
Hg for systolic and diastolic pressures for self-BP, 8.3/5.6
mm Hg for ambulatory BP, and 11.0/6.6 mm Hg for office
BP). Self-measured BP readings may be more reproducible
than ambulatory BP readings if they are taken under more
standardized conditions.
T.G. Pickering and W.B. White / Journal of the American Society of Hypertension 2(3) (2008) 119 –124
Comparison of office, ambulatory, and self (home) blood pressure monitoring
Predicts events
Diagnostic utility
Detects white coat and
masked hypertension
Evaluates the circadian
rhythm of BP
Evaluation of therapy
Normal limit for average
risk patients (mm Hg)
Yes (limited repeat uses)
130/80 (24-hour)
135/85 (awake)
120/75 (sleep)
Office BP
Yes (limited)
ABPM, abulatory blood pressure monitoring; BP, blood pressure.
Deciding When to Use Ambulatory and
Home BP Monitoring
Practical Considerations and Recommendations
BP measured over 24 hours by an ambulatory recording
is the best method for estimating an individual’s cardiovascular risk related to hypertension. This has been established
in a large number of prospective cohort studies,11–17 most of
which have shown that the office BP has negligible prospective value if the 24-hour BP is known. There are fewer
prospective studies using home BP,18 –21 and only two that
have compared ambulatory with self-BP monitoring (the
Ohasama14,19 and PAMELA studies18). Both of these studies found that the two methods had similar predictive value
for future cardiovascular events. In principle, one would
expect that 24-hour ambulatory BP would give a better
prediction of risk because there are important aspects of the
circadian profile of BP that are detected by ambulatory
recordings, but not by self/home BP measurements. These
include BP variability, the morning surge of BP, and the
related measures of dipping, and the nocturnal BP.24 Numerous studies have claimed that the nondipping pattern (a
diminution or reversal of the normal fall of BP during the
night), and a high nighttime BP predict risk independently
of the 24-hour level; other studies have not confirmed this.24
At the present time, there are no official guidelines relating
to the interpretation of these additional measures, and a
24-hour BP of 130/80 mm Hg and a self/home BP of 135/85
mm Hg are the useful cut-off points for patients in whom
antihypertensive therapy is being considered.24,25 In the
highest risk population, there are no official guidelines defining the ambulatory BP and self-BP equivalent of an office
BP of ⬍130/80 mm Hg.
An area where ABPM is particularly useful and superior
to self-BP monitoring is the evaluation of the efficacy of
antihypertensive drugs in clinical trials.26 –28 In clinical
practice, however, clinic and self monitoring of the BP are
the preferred methods for the clinical evaluation of re-
sponses to treatment, because performing multiple ABPM
sessions in the same patient is impractical.
Finding the Appropriate Monitor for
For both ambulatory and self-BP monitoring, use of the
upper arm is recommended.4 While wrist monitors are popular for self-BP monitoring by patients, they are generally
not recommended. Wrist monitors are limited by the need to
hold the device very still at the level of the heart; however,
in subjects with very obese upper arms, wrist monitors may
be the only practical method. Finger devices are not reliable.
It is essential that only monitors that have been independently validated for accuracy according to a well established
protocol be utilized. This is of particular relevance to
self-BP monitors, because there are many such devices on
the market that have not been independently tested. An
updated list is of validated monitors is available on the
educational website (http://www.dableducational.org/).
Manufacturers frequently change the model numbers of
self-BP devices, making it hard to know if the validation
results still apply. To remedy this, manufacturers are now
being asked to sign a Declaration of Blood Pressure Measuring Device Equivalence.
Means to Utilize Self/Home BP Monitoring in
Clinical Practice
It is of utmost importance to educate patients in the
proper use of their prescribed self/home BP devices. An
appropriate cuff size should be selected based on arm circumference according to American Heart Association
Guidelines for small, adult, and large adult cuff and bladder
assemblies.4,29 Patients should be instructed to take their
T.G. Pickering and W.B. White / Journal of the American Society of Hypertension 2(3) (2008) 119 –124
Office Blood Pressure
>140/90 mmHg in Low-risk Patients (no target organ disease)
>130/80 mmHg in High-risk Patients (target organ disease, diabetes)
Use of Ambulatory Blood Pressure
in Hypertension Management
Self-Monitored BP > 125/75 and
<135/85 mmHg
Self-Monitored BP <125/75 mmHg
Self-Monitored BP
Perform Ambulatory BP Monitoring
24-hour BP
³ 130/80 mmHg
24-hour BP <130/80 mmHg
³ 135/85 mmHg
Initiate Antihypertensive Therapy
Perform self/home or ambulatory BP monitoring
< Target BP
> Target BP
Non-drug therapy
Repeat self/home BP every 3 months
Repeat ambulatory BP every 1-2 years
Maintain present therapy
Change antihypertensive
therapy to improve control
(ABP target <130/80 mmHg)
(Self BP target < 135/85 mmHg)
Figure. Practical use of self/home BP monitoring and ABPM in clinical practice. Self-BP monitoring should be performed according
to strict guidelines prior to clinical decision-making (see text for details). Following antihypertensive therapy, the determination to use
self/home BP monitoring vs. ABPM is made according to availability, clinical judgment, and insurance coverage. ABPM, ambulatory
blood pressure monitoring; BP, blood pressure.
readings in the seated position (both legs on the floor, back
supported, arm supported at heart level) after resting for five
minutes. Three readings should be taken in succession (at
one minute intervals) both first thing in the morning (prior
to antihypertensive drugs) and in the evening (prior to
dosing of antihypertensive drugs, if taken at that time).
Duplicate readings taken in the morning and evening for
one week and recorded and averaged will yield self/home
BP values that can be utilized for diagnostic and therapeutic
purposes.29 Standing BPs can be obtained when indicated,
for instance in diabetic autonomic neuropathy, when orthostatic symptoms are present, or when a dose increase in
antihypertensive therapy has been made.
Using ABPM in Clinical Practice
While ABPM is not widely available in primary care
practice, it is generally offered by centers specializing in
hypertension or cardiovascular medicine. Ambulatory BP
measurement has particular utility in detection of masked
hypertension, white coat hypertension, and assessment of
antihypertensive therapy responses in patients on complex
antihypertensive treatment regimens. As noted previously,
ABPM is also the most effective means to determine the BP
values during sleep when nocturnal hypertension or nondipping profiles are suspected. Ambulatory monitoring studies
should be performed on typical working days if the patient
is employed; during the daytime it is advisable that the
patient refrain from sleeping, performing vigorous exercise,
and spending long periods of time driving (motion artifact).
Diaries or journals documenting times of wakefulness and
sleep as well as timing of antihypertensive medication doses
are useful for interpretation of the data.
The ambulatory BP devices may not work well in some
patients with very irregular cardiac rhythms including atrial
fibrillation, or in patients with rigid arteries such as dialysis
patients. In these individuals, the BPs should be compared
with those obtained with auscultatory devices when the
clinician is uncertain.
A schema showing how both self/home and ambulatory
BP measurements may be used in clinical practice is shown
in the Figure. Self-BP monitoring may be used as an initial
step to evaluate the out-of-office BP, and if ABPM is
available it is most helpful in cases where the self/home
BP is borderline (between 125/75 mm Hg and 135/85
mmHg).27,29,30 The target BP for self/home BP is usually
135/85 mm Hg for those whose target office BP is 140/90
T.G. Pickering and W.B. White / Journal of the American Society of Hypertension 2(3) (2008) 119 –124
mm Hg and 125/75 to 130/80 mm Hg for those whose target
office BP is 130/80 mm Hg.29 Equivalent values for ambulatory BP in low risk hypertensive patients are 130/80 mm
Hg for 24-hour BP, 135/85 mm Hg for the awake BP, and
125/75 mm Hg for the sleep BP.4
7. Imai Y, Otsuka K, Kawano Y, Shimada K, Hayashi H,
Tochikubo O, et al. Japanese society of hypertension
(JSH) guidelines for self-monitoring of blood pressure
at home. Hypertens Res 2003;26:771– 82.
8. 1999 World Health Organization-International Society
of Hypertension Guidelines for the Management of
Hypertension. Guidelines Subcommittee. J Hypertens
1999;17:151– 83.
9. Chobanian AV, Bakris GL, Black HR, Cushman WC,
Green LA, Izzo JL Jr, et al. The Seventh Report of the
Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure: the
JNC 7 Report. JAMA 2003;289:2560 –72.
10. Mengden T, Chamontin B, Phong Chau NG, Gamiz
JLP. Chanudet X and the participants of the First International Consensus Conference on Self-Blood Pressure Measurement. User procedure for self-measurement of blood pressure. Blood Press Monit 2000;5:
11. Dolan E, Stanton A, Thijs L, Hinedi K, Atkins N,
McClory S, et al. Superiority of ambulatory over clinic
blood pressure measurement in predicting mortality:
the Dublin outcome study. Hypertension 2005;46:156 –
12. Perloff D, Sokolow M, Cowan R. The prognostic value
of ambulatory blood pressures. JAMA 1983;249:2792–
13. Verdecchia P, Porcellati C, Schillaci G, Borgioni C,
Ciucci A, Battistelli M, et al. Ambulatory blood pressure. An independent predictor of prognosis in essential
hypertension [erratum in 1995;25:462]. Hypertension
1994;24:793– 801.
14. Ohkubo T, Imai Y, Tsuji I, Nagai K, Watanabe N,
Minami N, et al. Prediction of mortality by ambulatory
blood pressure monitoring versus screening blood pressure measurements: a pilot study in Ohasama. J Hypertens 1997;15:357– 64.
15. Bjorklund K, Lind L, Zethelius B, Andren B, Lithell H.
Isolated ambulatory hypertension predicts cardiovascular morbidity in elderly men. Circulation 2003;107:
16. Clement DL, De Buyzere ML, De Bacquer DA, de
Leeuw PW, Duprez DA, Fagard RH, et al, Office versus
Ambulatory Pressure Study Investigators. Prognostic
value of ambulatory blood-pressure recordings in patients with treated hypertension. N Engl J Med 2003;
17. Kario K, Pickering TG, Umeda Y, Hoshide S, Hoshide
Y, Morinari M, et al. Morning surge in blood pressure
as a predictor of silent and clinical cerebrovascular
disease in elderly hypertensives: a prospective study.
Circulation 2003;10:1401– 6.
18. Mancia G, Facchetti R, Bombelli M, Grassi G, Sega R.
Long-term risk of mortality associated with selective
and combined elevation in office, home, and ambula-
This article was reviewed by Giuseppe Mancia, MD and
Sheldon G. Sheps, MD.
The American Society of Hypertension Writing Group
Steering Committee: Thomas D. Giles, MD; Chair, Henry
R. Black, MD; Joseph L. Izzo, Jr, MD; Barry J. Materson,
MD, MBA; Suzanne Oparil, MD; and Michael A. Weber,
1. Ayman D, Goldshine AD. Blood pressure determinations by patients with essential hypertension. I. The
difference between clinic and home readings before
treatment. Am J Med Sci 1940;200:465–74.
2. O’Brien E, Waeber B, Parati G, Staessen J, Myers MG.
Blood pressure measuring devices: recommendations
of the European Society of Hypertension. BMJ 2001;
3. Pickering T. Recommendations for the use of home
(self) and ambulatory blood pressure monitoring.
American Society of Hypertension Ad Hoc Panel. Am J
Hypertens 1996;9:1–11.
4. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J,
Hill MN, et al. Recommendations for blood pressure
measurement in humans and experimental animals: part
1: blood pressure measurement in humans: a statement
for professionals from the Subcommittee of Professional and Public Education of the American Heart
Association Council on High Blood Pressure Research.
Circulation 2005;111:697–716.
5. Williams B, Poulter NR, Brown MJ, Davis M, McInnes
GT, Potter JF, et al. Guidelines for management of
hypertension: report of the fourth working party of the
British Hypertension Society, 2004-BHS IV. J Hum
Hypertens 2004;18:139 – 85.
6. Mancia G, De Backer G, Dominiczak A, Cifkova R,
Fagard R, Germano G, et al, The task force for the
management of arterial hypertension of the European
Society of Hypertension, The task force for the management of arterial hypertension of the European Society of Cardiology. 2007 Guidelines for the management
of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2007;28:1462–
25. Mansoor GA, White WB. Self-measured home blood
pressure in predicting ambulatory hypertension. Am J
Hypertens 2004;17:1017–22.
26. White WB. Ambulatory blood pressure monitoring for
the assessment of antihypertensive therapy in clinical
trials. In: White WB, editor. Blood pressure monitoring
in cardiovascular medicine and therapeutics. Totowa,
New Jersey: Springer-Verlag/Humana Press, Ltd, 2007:
437– 62.
27. White WB, Giles T, Bakris GL, Neutel JM, Davidai G,
Weber MA. Measuring the efficacy of antihypertensive
therapy by ambulatory blood pressure monitoring in the
primary care setting. Am Heart J 2006;151:176 – 84.
28. White WB, Mansoor GA, Pickering TG, Vidt DG,
Hutchinson HG, Johnson RB, et al. Differential effects
of morning and evening dosing of nisoldipine ER on
circadian blood pressure and heart rate. Am J Hypertens
1999;12:806 –14.
29. Pickering TG, Houston Miller N, Ogedegbe G, Krakoff
LR, Artinian NT, Goff D. Call to action on use and
reimbursement for home blood pressure monitoring. A
joint statement by the American Heart Association,
American Society of Hypertension, and the Preventive
Cardiovascular Nurses’ Association. Hypertension
2008. Forthcoming.
30. White WB. Ambulatory blood pressure monitoring in
clinical practice. N Engl J Med 2003;348:2377–78.
tory blood pressure. Hypertension 2006;47:846
Ohkubo T, Imai Y, Tsuji I, Nagai K, Kato J, Kikuchi N,
et al. Home blood pressure measurement has a stronger
predictive power for mortality than does screening
blood pressure measurement: a population-based observation in Ohasama, Japan. J Hypertens 1998;16:971–
Bobrie G, Chatellier G, Genes N, Clerson P, Vaur L,
Vaisse B, et al. Cardiovascular prognosis of “masked
hypertension” detected by blood pressure self-measurement in elderly treated hypertensive patients. JAMA
2004;291:1342– 49.
Stergiou GS, Baibas NM, Kalogeropoulos PG. Cardiovascular risk prediction based on home blood pressure
measurement: the Didima study. J Hypertens 2007;25:
1590 –96.
Pickering TG, Eguchi K, Kario K. Masked hypertension: a review. Hypertens Res 2007;30:479 – 88.
Stergiou GS, Baibas NM, Gantzarou AP, Skeva II,
Kalkana CB, Roussias LG, et al. Reproducibility of
home, ambulatory, and clinic blood pressure: implications for the design of trials for the assessment of
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15:101– 4.
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T.G. Pickering and W.B. White / Journal of the American Society of Hypertension 2(3) (2008) 119 –124
Journal of the American Society of Hypertension 2(6) (2008) 484 – 494
ASH Position Article
Hypertension in pregnancy
Marshall D. Lindheimer, MDa, Sandra J. Taler, MDb, and F. Gary Cunningham, MDc
Departments of Obstetrics & Gynecology and Medicine, University of Chicago Pritzker School of Medicine, Chicago, Illinois, USA;
Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA; and
Department of Obstetrics & Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Manuscript received April 15, 2008 and accepted September 1, 2008
Hypertension complicates 5% to 7% of all pregnancies. A subset of preeclampsia, characterized by new-onset hypertension,
proteinuria, and multisystem involvement, is responsible for substantial maternal and fetal morbidity and is a marker for future
cardiac and metabolic disease. This American Society of Hypertension (ASH) position paper summarizes the clinical spectrum
of hypertension in pregnancy, focusing on preeclampsia. Recent research breakthroughs relating to etiology are briefly
reviewed. Topics include classification of the different forms of hypertension during pregnancy, and status of the tests
available to predict preeclampsia, and strategies to prevent preeclampsia and to manage this serious disease. The use of
antihypertensive drugs in pregnancy, and the prevention and treatment of the convulsive phase of preeclampsia, eclampsia,
with intravenous MgSO4 is also highlighted. Of special note, this guideline article, specifically requested, reviewed, and
accepted by ASH, includes solicited review advice from the American College of Obstetricians and Gynecologists. J Am Soc
Hypertens 2008;2(6): 484 – 494. © 2008 American Society of Hypertension. All rights reserved.
Keywords: Preeclampsia; eclampsia; blood pressure; obstetrics.
Hypertension, complicating 5% to 7% of all pregnancies,
is a leading cause of maternal and fetal morbidity, particularly when the elevated blood pressure (BP) is due to preeclampsia, either alone (pure) or “superimposed” on chronic
vascular disease.1,2 Preeclampsia is a major cause of preterm birth and an early marker for future cardiovascular and
metabolic diseases, whereas preterm delivery is associated
with immediate neonatal morbidity and has been linked to
remote cardiovascular and metabolic disease in the newborns.2– 6 This bleak clinical picture and its large economic
burden has been known for decades. Still, even in the
current millennium, the hypertensive disorders of pregnancy remain among the most understudied areas and one of
the lowest recipient of research funds compared with other
diseases in terms of disability adjusted life years.7 This
dearth of research progress is a major factor underscoring
decades of controversies that surrounded the classification,
diagnosis, and management of the hypertensive disorders of
Conflict of interest: none.
Corresponding author: ASH Writing Group, ASH Office, 148
Madison Avenue, 5th Floor, New York, New York, 10016. Tel:
212-696-9099; fax: 212-696-0711.
E-mail: [email protected]
pregnancy. More recently, we have witnessed an upsurge of
investigative interest and achievements, mainly in regard to
preeclampsia. In addition, national working groups have
presented consensus documents aimed at achieving consistency in diagnosis and management of these diseases.8 –11
One example is the National High Blood Pressure Education Program (NHBPEP) report, last updated in 2000,10 and
coordinated with more recent practice bulletins of the
American College of Obstetricians and Gynecologists.12
This American Society of Hypertension, Inc. (ASH) position paper presents a précis of the hypertensive disorders
complicating pregnancy, including whether they can be
predicted and/or prevented, and guidelines for their management. It also incorporates solicited input from the American College of Obstetrics and Gynecology.
Cardiovascular and Volume Changes in Normal
Striking alterations in both cardiovascular function and
volume homeostasis occur during normal pregnancy;
knowledge of these normal adaptations is requisite to the
early detection and optimal management of preexisting or
new-onset disease.13–15 Large increments in cardiac output,
1933-1711/08/$ – see front matter © 2008 American Society of Hypertension. All rights reserved.
M.D. Lindheimer et al. / Journal of the American Society of Hypertension 2(6) (2008) 484 – 494
systolic or 90 mm Hg diastolic, diastolic levels of 75 mm
Hg in the first and 85 mm Hg in the second trimester or
systolic values of 120 mm Hg in mid-pregnancy and 130
mm Hg in late gestation may be abnormally elevated for
some women.16 –18 In this respect, data from two studies
(totaling ⬎30,000 women) suggest that diastolic pressures
⬎85 mm Hg or mean arterial pressures of ⱖ90 mm Hg at
any stage of gestation are associated with significant increases in fetal mortality.16,17 Another caveat is that the rise
in glomerular filtration rate (GFR) that normally occurs in
pregnancy results in lower levels of creatinine and urea
nitrogen. Failure to appreciate this (eg, failure to appreciate
that creatinine levels of 0.9 or 1 mg/dL are abnormal in
gestation) may lead one to miss evidence of preexisting
nephrosclerosis or other renal diseases; the latter disorders
are associated with higher incidences of superimposed and
often severe preeclampsia. Finally, the marked stimulation
of the RAAS in normal pregnancy combined with few
published data to differentiate between the normally or
excessively aldosterone levels in gestation makes diagnoses of primary aldosteronism difficult.15
Measurement of BP
Figure. Systolic and diastolic blood pressures in relation to
gestational age in 6,000 White women 25 to 34 years of age
who delivered single-term infants. Reprinted with permission
from Christianson RE. Studies on blood pressure during pregnancy. I. Influence of parity and age. Am J Obstet Gynecol
1976;125:509 –13.
accompanied by marked increases in intravascular and extracellular volume, occur rapidly during the first half of
pregnancy, then plateau or rise more slowly thereafter. BP
falls, with decrements starting in early gestation and reaching a nadir near mid-pregnancy (Figure). The decrease in
pressure is modest compared with the increases in cardiac
output and intravascular volume, mainly because of concurrent large increase in global vascular compliance.14 Other
changes include early renal vasodilatation and hyperfiltration, and marked stimulation of the renin-angiotensin-aldosterone system (RAAS).13,15 The latter is characterized by
high levels of all measured elements of the RAAS chain,
which react appropriately to volume-change stimuli around
new steady-state set points.15 There are also marked increases in free levels of other corticoids including those
with both sodium retaining (eg, desoxycorticosterone) and
natriuretic (eg, progesterone) potential.15
Clinical relevance of these changes includes the following. Undiagnosed chronic hypertension may be masked in
early pregnancy because of the initial decrease in pressure,
then misdiagnosed as a gestation specific disorder when
abnormal values appear later in pregnancy. Though hypertension in pregnancy remains defined as a BP ⱖ140 mm Hg
Previous methodologic controversies have been resolved,
with the current consensus being that BP during pregnancy
is best measured with the woman sitting quietly for several
minutes, the arm cuff at heart level, and diastolic pressure
designated at the 5th Korotkoff sound. It is now apparent
that the lower levels associated with measurements recorded
when subjects are positioned in lateral recumbence merely
reflect differences in hydrostatic pressure when the cuff is
positioned substantially above the left ventricle (reviewed
elsewhere).14 Older views suggesting that gravid women
manifest large differences between the 4th Korotkoff (muffling) and 5th Korotkoff (disappearance), with the latter
occasionally approaching zero because of their hyperdynamic circulations, have been disproved, and 5th Korotkoff
has been established as the sound closest to true diastolic
Hypertension is defined as levels that are ⱖ140 mm Hg
systolic or ⱖ90 mm Hg diastolic (preferably confirmed by
two readings 4 to 6 hours apart).11,12 Previously, an increase
of 15 mm Hg diastolic and 30 mm Hg systolic, respectively,
even if the final value ⱖ140/90 mm Hg was also included in
the definition. However, data demonstrating that outcomes
are similar irrespective of the magnitude of rise when values
remain below 140/90 mm Hg, have led consensus groups to
delete this latter definition. Nevertheless, the NHBPEP consensus report11 stressed that patients with BPs below the
140/90 mm Hg cut-off who have experienced a 30 or 15 mm
Hg rise in systolic and diastolic levels, respectively, be
managed as high-risk patients. Of interest, these differences
in defining hypertension are one reason for discordant find-
M.D. Lindheimer et al. / Journal of the American Society of Hypertension 2(6) (2008) 484 – 494
ing in areas such as epidemiology and outcome research,
now hopefully resolved.
Classifying Hypertension in Pregnancy
after manifest other signs and symptoms of that disorder).
Although the cause of gestational hypertension is unclear,
this entity appears to identify women destined to develop
essential hypertension later in life (analogous to the relationship of gestational diabetes to the subsequent development later in life of type 2 diabetes mellitus).24,25 BP returns
to normal, during the immediate puerperium (at which point
some relabel the entity transient hypertension). Many of
these women are hypertensive in one, some, or all of their
subsequent pregnancies.
There is an entity termed late postpartum hypertension
that describes women with normotensive gestations who
develop high BP (usually mild) several weeks to 6 months
after delivery that normalizes by the end of the first postpartum year.15 Little is known about this entity, though it
also may predict essential hypertension later in life. Finally,
a very rare group of patients harbor activating mineralocorticoid receptor mutations that result in an exaggerated sensitivity to the usually weak effect of progesterone.26 These
women manifest early salt-sensitive hypertension, coincident with the rapid rise in progesterone production during
the initial trimester.
Caregivers have been and continue to be confused by the
multiple terminologies, some complex and detailed, used to
classify the hypertensive disorders of pregnancy. For example, the terms toxemia, gestosis, pregnancy-induced hypertension, and preeclamptic toxemia have each been used to
classify the disorder we will label preeclampsia. The same
term might have different meanings depending on the
schema in which it was published. For example, pregnancyinduced hypertension could signify both gestational hypertension and preeclampsia to some, whereas others require
pregnancy-induced hypertension plus proteinuria to signify
preeclampsia. The terminology used here is that recommended by the NHBPEP Working Group11 and is concise
and practical. In it, BP in pregnancy is considered in only
four categories:
Chronic hypertension of any cause.
Preeclampsia superimposed on chronic hypertension.
Gestational hypertension.
Preeclampsia, pure or superimposed (categories 1 and 3), is
the disorder most often associated with severe maternal-fetalneonatal complications (including fatalities). Most women in
category 2 have essential hypertension, mostly mild (ⱕ105
mm Hg) in intensity, their pregnancies usually (but not invariably) uncomplicated. On occasion, the high BP is secondary,
from known causes including endocrine tumors, renal artery
stenosis, and renal disease, and some of these pregnancies do
poorly. Pheochromocytoma, though rare, may present for the
first time during pregnancy and is especially lethal when unsuspected, but if diagnosed it can be managed to a successful
outcome, either surgically or pharmacologically, depending on
the stage of gestation.20,21 Cushing’s syndrome, also rare, has
been associated with exacerbations of hypertension during
pregnancy and poor fetal outcomes,20,22 and anecdotal reports
of serious and fatal complications in pregnant women with
scleroderma and periarteritis nodosa, particularly when these
latter disorders involve the kidneys.15 On the other hand,
pregnancy may diminish the kaliuresis and BP rise associated with primary aldosteronism, perhaps related to the
increase in circulating progesterone levels, hypertension,
and hypokalemia represented postpartum when progesterone levels decline.20,23 Finally, angioplasty and stent placement have been successfully performed on pregnant women
with renal artery stenosis.20
Gestational hypertension is characterized by mild to moderate elevation of BP after mid-gestation but without abnormal proteinuria, usually near term (though more severe
forms of hypertension have been described, and some of
these patients are actually preeclamptics who shortly there-
The Clinical Spectrum of High BP in Pregnancy
Most women with chronic hypertension have uneventful
gestations as long as their BP remains at (or is controlled to)
levels considered “mild to moderate.” In contrast, preeclampsia is associated with many serious complications.
Thus, early and accurate recognition and differentiation of
preeclampsia from other causes of high BP in pregnancy has
important implications regarding management. A precise
diagnosis, however, is not always possible, in which case it
is best to manage the woman as if she has preeclampsia,
which is the more serious disorder with a broad clinical
Preeclampsia, a protean disorder that involves many organ systems, is primarily characterized by hypertension and
proteinuria. The latter is defined by excretion of ⱖ300
mg/24 hours, a urine protein/creatinine ratio of ⱖ0.3, or a
qualitative 1⫹ dipstick reading. The dipstick value of 1⫹
has many false-positive and false-negative results and is the
least useful.11,19 Accurate, timed urine collections are very
difficult to obtain during pregnancy, and, theoretically, a
urine creatinine/protein ratio eliminates such errors. However, the accuracy of this test is still being investigated.
Preeclampsia may also be accompanied by rapid weight
gain and edema, appearance of coagulation or liver function
abnormalities, and occurs most often in nulliparas, usually
after gestational week 20, and most frequently near term.
Attempts have been made to categorize preeclampsia as
“mild” or “severe” (Table 1).11,27 The latter are often defined on the basis of BP levels (ⱖ110 mm Hg diastolic and
160 mm Hg systolic), the appearance of nephrotic range
proteinuria, sudden oliguria, neurologic symptoms (eg,
M.D. Lindheimer et al. / Journal of the American Society of Hypertension 2(6) (2008) 484 – 494
Table 1
Preeclampsia: judging severity*
Diastolic BP
Visual disturbances
Abdominal pain
SCreatinine (GFR)
Nonreassuring fetal
More Severe
wk 34
⬍100 mm Hg
wk 35
⬎110 mm Hg
Nephrotic range
(⬎3 g/24 h)†
Mild to
often preceded by premonitory signs including headache,
visual disturbances, epigastric pain, constricting sensations
in the thorax, apprehension, excitability, and hyperreflexia.
However, convulsions can occur suddenly and without
warning in a seemingly stable patient with no apparent or
only minimal elevations of BP.31 In fact, the capricious
nature of this disorder makes early hospitalization of
women with suspected preeclampsia advisable. Most
eclamptic convulsions occur prepartum, intrapartum, or
within 48 hours postpartum, but there is an unusual entity
labeled late postpartum eclampsia that occurs from 48
hours to several weeks after delivery.32
One complication, affecting approximately 5% of women
with preeclampsia that can progress rapidly to life-threatening condition, is the “HELLP” syndrome which is characterized by all or some of the following signs: Hemolysis,
abnormal Elevation of Liver enzyme levels (aspartate aminotransferase and lactic dehydrogenase may increase
quickly, the latter to ⬎1,000 IU/dL), and Low Platelet
counts (also evolving rapidly and decreasing to ⬍40,000/
mL), with schistocytes present on the blood smear.13,15,33
The HELLP syndrome may at first appear deceptively benign, with initial enzyme elevations and thrombocytopenia
of borderline severity. Such presentations require inpatient
management, often termination of the pregnancy if the disease progresses, and, although postpartum recovery is usually rapid, the disease may persist for almost a week.
Less Severe
AST, aspartate aminotransferase; BP, blood pressure; GFR, glomerular filtration rate; LDH, lactic acid dehydrogenase.
* Presence of convulsions (eclampsia), congestive heart failure,
or pulmonary edema are always very ominous signs.
Degree of proteinuria alone may not indicate seriousness unless accompanied by other ominous sign or symptom.
Growth restriction, adverse signs during periodic fetal testing
including electronic monitoring and Doppler ultrasound.
The American College of Obstetrics and Gynecology bulletins
utilize the terms “mild” and “severe” for our preferred “less” and
“more” severe, so as to underscore diligence for any form of
headache, hyperreflexia), and laboratory tests demonstrating
thrombocytopenia (defined as ⬍100,000 per microLiter),
hemolysis, or abnormal liver function (including presence
of schistocytes, hyperbilirubinemia, or elevated aspartate
aminotransferase and lactic acid dehydrogenase levels), although the magnitude of proteinuria alone as a predictor of
severity has been questioned.27,28 Because a woman with
seemingly mild disease (eg, a teenage gravida with a BP of
140/90 mm Hg and minimal proteinuria) can suddenly convulse, designations such as mild and severe can be misleading. In fact, de novo hypertension alone occurring after
mid-gestation in a nullipara is sufficient reason to manage
the patient as if she were preeclamptic.
Early preeclampsia (onset ⬍34 weeks’ gestation) is associated with greater morbidity than when the disorder
presents at term. In this respect, some suggest subdividing
preeclampsia into two groups by time of onset because of
differences in prognosis and management.29 Such a distinction may be misleading, however, because all preeclampsia
is potentially explosive.
The eclamptic convulsion, a dramatic and life-threatening
complication of preeclampsia, was once associated with a
maternal mortality of 30%.13,15 More recently, and primarily in developed nations, improved and aggressive obstetric
management has decreased the occurrence of convulsions
and made maternal deaths unusual.1,13,15,30 Eclampsia is
Pathogenic Mechanism in Preeclampsia
Preeclampsia has been dubbed the disease of theories, but
recent progress concerning pathogenesis of its clinical phenotypes suggests breakthroughs that may lead to accurate prediction, prevention, and better treatments. Discussion of all etiologic theories (ie, altered cell and molecular biology of the
placenta, antioxidants, the systemic inflammatory response,
humeral and immune factors, and cardiovascular maladaptations to gestation) is beyond the scope of this article and
reviewed in detail by others.8,15,34 The most plausible theories
focus on the placenta and describe the disorder in two stages.
In the first, the initiating cause results in the placenta producing
factors (eg, specific proteins, trophoblastic debris) that enter
the maternal circulation. The second stage, called maternal, is
overt disease that depends not only on the action of these
circulating factors, but also the health of the mother, including
diseases that may affect the vasculature (preexisting cardiorenal, metabolic, and genetic factors; obesity). A promising research area in 2008 involved elucidation of the role of antiangiogenic factors produced by the placenta in the pathogenesis
of preeclampsia phenotypes.8,15,34 –36
Placentas of women destined to develop preeclampsia overproduce at least two antiangiogenic proteins that reach abnormally high levels in the maternal circulation. One soluble
Fms-like tyrosine kinase 1 (sFlt-1) is a receptor for placental
growth (PIGF) and vascular endothelial growth (VEGF) fac-
M.D. Lindheimer et al. / Journal of the American Society of Hypertension 2(6) (2008) 484 – 494
The best descriptions of the gross and microscopic brain
pathology in eclampsia can be found in the extensive autopsy series of Sheehan and Lynch,42 because most of these
necropsies were performed within 2 hours of death, thereby
eliminating the rapid autolytic postmortem changes that
might confound interpretation. They noted little evidence of
brain edema and postulated that brain swelling was a late
rather than a causal event. The major findings, however,
were both gross and microscopic evidence of bleeding.
Previous controversy regarding the pathogenesis of
eclampsia centered on whether it was a unique entity, due
mainly to severe vasoconstriction (occasionally localized in
the cerebral circulation) or more akin to hypertensive encephalopathy appears to have been resolved. Studies using
sophisticated imaging techniques reveal increased cerebral
blood flow in preeclamptic women, whereas data derived
from animal models suggest that eclamptic women have
increased perfusion pressures, perhaps exceeding the cerebral circulation’s autoregulatory capacity, and that their
vessels “leak” at perfusion pressures lower than what would
be expected in nonpregnant subjects.13,15,43,44 Reports
based on computed axial tomography and magnetic resonance imaging describe transient abnormalities consistent
with localized hemorrhage or edema,45 with the latter described as vasogenic and fully reversible, but occasionally
“cytotoxic” accompanied by infarction with lesions that
The Multisystemic Pathophysiology and
Pathology of Preeclampsia
remodel and dilate.41 This aberration underlies theories that
restriction of placental blood flow leads to a relatively
hypoxic uteroplacental environment, with subsequent
events mediated through hypoxemia-induced genes resulting in the release of factors (eg, antiangiogenic proteins)
that enter the mother’s circulation and initiate the maternal
tors. Increased maternal sFlt-1 levels decrease circulating free
PlGF and VEGF concentrations leading to endothelial dysfunction. The second antiangiogenic protein, soluble endoglin
(sEng) may impair the binding of transforming growth factor-␤1 to endothelial receptors, thereby decreasing endothelial
nitric oxide– dependent vasodilatation. Simultaneous introduction of adenoviruses encoding both sFlt-1 and sEng into pregnant rats produces severe hypertension, heavy proteinuria, elevated liver enzyme levels, and circulating schistocytes—in
essence creating a powerful rodent model that simulates most
of the protean manifestations of preeclampsia in humans and
has obvious implications for the study of mechanisms and
subsequent therapy of this disease.35–37
The cause of placental overproduction of these proteins,
however, remains an enigma. Research currently focusing
on immunological mechanisms (eg, HLAG, natural killer
cells, autoantibodies agonistic to the angiotensin I receptor),
oxidative stress, mitochondrial pathology, and hypoxia
genes.8,15,34 In essence, research in this area, dormant for
decades, is now quite promising.
BP and the Cardiovascular System
Hypertension in preeclampsia is due primarily to marked
vasoconstriction, because both cardiac output and arterial
compliance are reduced.14,15,19 There is a reversal of the
normal circadian rhythm, with the highest BP now at night,
and a loss of the normal pregnancy-associated refractoriness
to pressor agents; the sensitivity to infused Ang II increasing weeks before overt disease.15 Explanations for the increased reactivity to Ang II include up-regulation of receptor sensitivity, synergy with circulating autoantibodies
agonistic to the angiotensin type 1 receptor,15,34,38,39 and
decreases in the level of circulating Ang 1–7. Increases in
insulin resistance and sympathetic nervous system tone also
occur and have been implicated in the vasoconstriction
characteristic of preeclampsia.15
As noted, renal hemodynamics increase markedly in normal gestation. Renal plasma flow (RPF) and GFR decrease
in preeclampsia (⬃25%); thus, values may still be above or
at those measured in the nonpregnant state.15 The decrement
in RPF is attributable to vasoconstriction, whereas the fall in
GFR relates both to the decrement of RPF and the development of a glomerular lesion termed glomerular endotheliosis (detailed elsewhere).15,24,34,40
Shallow and abnormal placentation is a hallmark of preeclampsia, highlighted by a failure of the normal trophoblastic invasion of the spiral arteries, these vessels failing to
Liver and Coagulation Abnormalities
Preeclampsia is associated with activation of the coagulation system, with thrombocytopenia (usually mild) as the
most commonly detected abnormality. There is increased
platelet activation and size, plus decrements in their lifespan. The hypercoagulability of normal pregnancy is accentuated (eg, reduced antithrombin III, protein S, and protein
C) even when platelet counts appear normal.15,46 However,
occasionally, the coagulopathy can be severe, as detailed in
the ominous HELLP syndrome discussed previously.
Preeclampsia also affects the liver.13,15 Manifestations
include elevated aspartate aminotransferase and lactic dehydrogenase levels, the increments usually small, except
when the HELLP syndrome supervenes. The gross hepatic
changes in preeclampsia, also detailed in the autopsy series
of Sheehan and Lynch,42 are petechiae ranging from occasional to confluent areas of infarction, as well as subcapsular
M.D. Lindheimer et al. / Journal of the American Society of Hypertension 2(6) (2008) 484 – 494
Prediction and Prevention of Preeclampsia
Network) was completed in late 2008 and is scheduled to be
reported in early 2009.53,54
There are several unresolved controversies regarding
treatment of the hypertensive disorders of pregnancy, and
the hypertensive expert called to consult should be aware of
them. If disagreements occur, it is prudent to note that it is
the obstetrician who has been managing the pregnancy for
months, who is responsible for both the mother’s and fetus’
outcomes and who may be required to defend bad outcomes
to official committees and boards.
hematomas, some having ruptured and caused death. Hematomas were, however, unusual in a later study whose
investigators assessed the liver laparoscopically.47 The
characteristic microscopic lesion is periportal, manifesting
as hemorrhage into the hepatic cellular columns and at times
concurrent infarction. Material obtained by laparoscopicguided biopsies show substantial intracellular fatty changes
in all patients with preeclampsia, regardless of the severity
of the disease.46 However, autopsy and laparoscopy studies
are by their nature quite selective.
Suspicion of preeclampsia is sufficient reason to recommend hospitalization, given the disease’s potential to accelerate rapidly.11,13,15,55 This approach will minimize diagnostic
error, diminish the incidence of convulsions, and improve fetal
outcome. Because delivery remains the only known “cure,”
and maternal and fetal disease status may change rapidly, we
recommend the following. Near term, induction of labor is the
therapy of choice, whereas attempts to temporize should be
made if pregnancy is at an earlier stage. If the latter decision is
made, and BP rises to unacceptable levels, several antihypertensive agents considered safe in pregnancy are available and
are discussed in the following sections (Table 2). Delivery is
indicated at any stage of pregnancy if severe hypertension
remains uncontrolled for 24 to 48 hours or at the appearance of
certain “ominous” signs such as clotting or liver abnormalities,
decreasing renal function, signs of impending convulsions
(headache, epigastric pain, and hyperreflexia), or the presence
of severe growth retardation or nonreassuring fetal testing
(Table 1). Preeclampsia remote from term is a special situation
in which the patients should be hospitalized and closely monitored in tertiary obstetric care centers (preferably those with
prenatal close observation units), facilities not readily available
to many practitioners.56 Gestation is permitted to continue as
long as BP is controlled, no ominous signs of life-threatening
maternal complications occur, and in the absence of signs of
nonreassuring fetal testing.
Numerous studies have evaluated tests to predict preeclampsia or to distinguish it from more benign hypertensive complications. They include evaluation of circulating
or urinary markers and imaging techniques. In one large
systematic literature review, the authors concluded that
none of the screening methods tested through 2004 were
clinically useful predictors of preeclampsia, and that analyzing combinations of tests might prove more valuable.48
That review did not include a more recent literature assessing circulating or urinary antigenic and antiangiogenic proteins. The more recent studies have generated hope that
combinations of sFlt-1, sEng, and PlGF will provide the
sensitivities and likelihood ratios required for prediction of
preeclampsia and may prove useful in its differential diagnosis as well.49 Several of these studies demonstrated prediction with very high sensitivities, especially combinations
of serum SFlt-1, sEng, and PlGF, but the vast majority of
these data come from retrospective analyses of banked specimens from earlier trials. By early 2008, there were several
ongoing prospective observational studies in progress.
Numerous interventions have been proposed to prevent
preeclampsia, usually predicated on theories that administration of a drug, mineral, or vitamin will inhibit or reverse
a presumed causal mechanism. Systematic reviews through
early 2008, however, identified only two interventions that
have some minimal protective effects.50 –52 Low-dose aspirin may reduce the incidence of preeclampsia approximately
10%, but the numbers needed to treat to avoid adverse
outcomes are large.51 Calcium supplementation has a small
effect in populations with low dietary calcium intake (less
than 600 mg/d).52 In these latter populations, the incidence
of the disorder does not decrease, but there are small but
significant decrements in serious adverse advents including
fetal demise. Supplementation with the antioxidant vitamins
C and E has had no effects to date, and has even proved
harmful in certain high-risk populations, though the largest
of these trials (by National Institute of Child Health and
Development [NICHD] Maternal Fetal Medicine Trials
Sudden Escalating Hypertension and Imminent or
Frank Eclampsia
Controversies remain as whether to and at what level to
treat rapidly rising BP near term or during delivery (a
phenomenon often indicating the appearance of pure or
superimposed preeclampsia). There is further debate on
how aggressively to lower the BP. The NHBPEP recommendations11 state that diastolic levels ⬎105 mm Hg require treatment (though some contemporary texts still
recommend ⬎110 mm Hg), with some reservations. Circumstances, such as a teenager whose recent diastolic levels
were 70 mm Hg or lower, or patients demonstrating signs
M.D. Lindheimer et al. / Journal of the American Society of Hypertension 2(6) (2008) 484 – 494
Table 2
Drugs for chronic hypertension in pregnancy
Concerns or Comments
Methyldopa (B)
0.5–3.0 g/d in 2 divided
Labetalol (C)†
200–1200 mg/d in 2–3
divided doses
30–120 mg/d of a slowrelease preparation
50–300 mg/d in 2–4
divided doses
Drug of choice according to NHBEP working group; safety after first
trimester well documented, including 7-year follow-up evaluation
of offspring.
Gaining in popularity as concerns relating to growth restriction and
neonatal bradycardia do not seem to have materialized.
May inhibit labor and have synergistic interaction with magnesium
sulfate; small experience with other calcium-entry blockers.
Few controlled trials, long experience with few adverse events
documented, useful only in combination with sympatholytic agent;
may cause neonatal thrombocytopenia.
May cause fetal bradycardia and decrease uteroplacental blood flow,
this effect may be less for agents with partial agonist activity; may
impair fetal response to hypoxic stress; risk for growth retardation
when started in first or second trimester (atenolol).
Majority of controlled studies in normotensive pregnant women rather
than hypertensive patients, can cause volume depletion and
electrolyte disorders; may be useful in combination with
methyldopa and vasodilator to mitigate compensatory fluid
Use associated with major anomalies plus fetopathy, oligohydramnios,
growth restriction, and neonatal anuric renal failure, which may be
Nifedipine (C)
Hydralazine (C)
Depends on specific agent
Hydrochlorothiazide (C)
25 mg/d
Contraindicated ACE
inhibitors and AT1receptor antagonists
␤-receptor blockers (C)
Drug (Food and Drug
Administration risk)*
ACE, angiotensin-converting enzyme; NHBEP, National High Blood Pressure Education Program.
Note: No antihypertensive drug has been proven safe for use during the first trimester. Drug therapy is indicated for uncomplicated chronic
hypertension when diastolic blood pressure is ⱖ100 mm Hg (Korotkoff V). Treatment at lower levels may be indicated for patients with
diabetes mellitus, renal disease, or target organ damage.
* U.S. Food and Drug Administration classification.
We omit some agents (eg, clonidine, ␣-blockers) because of limited data on use for chronic hypertension in pregnancy.
We would classify in category X during second and third trimesters.
Reprinted with permission from Alpern RJ, Hebert SC. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology, 4th ed. San
Diego, California: Academic Press, Elsevier, 2008: 2386.
cardiac decompensation, or cerebral symptoms such as excruciating headache, confusion, or somnolence, warrant
treatment at lower levels.11,13,15
Management of eclamptic convulsions requires parenteral magnesium sulfate administration, which is shown to
be superior to either diazepam or phenytoin for both prevention and treatment.13,15,51,57 However, there is no unanimity as when and who to treat prophylactically. Intravenous magnesium is not without hazard, and some contend
its risks outweigh those associated with “mild” preeclampsia and that it should be reserved for women with severe
disease.58 Trials to settle these questions are still needed.
Chronic Hypertension
Most pregnant women with chronic hypertension have
the “essential” variety, with their disease mild in nature and
of recent origin. The majority of these gestations are uncomplicated, though outcomes are worse than women with
normotensive pregnancies.13,15,20 Chronic hypertension is
associated with increased incidences of placental abruption,
acute renal failure, cardiac decompensation, and cerebral
accidents in the mother and of growth retardation and unexplained mid-trimester fetal death. Such events are mainly
associated with superimposed preeclampsia, whose incidence in chronic hypertensives is ⱖ20%.59 Risk for complications correlates with the age of the mother, the duration
and degree of control of her high BP, and the presence of
end-organ damage. Extremely obese women with chronic
hypertension are at special risk for cardiac decompensation
near term, and especially if volume loaded during labor.
Echocardiography performed earlier in pregnancy may alert
the physician to patients at risk with early evidence of
ventricular dysfunction.
The approach to treatment of women with chronic hypertension is also controversial. Although all would treat
women with severe hypertension, opinions vary as to
whether to treat mild hypertension. In this respect, systemic
reviews of randomized studies to date suggest that treatment
M.D. Lindheimer et al. / Journal of the American Society of Hypertension 2(6) (2008) 484 – 494
Table 3
Drugs for urgent control of severe hypertension in pregnancy
Drug (Food and Drug
Administration risk)*
Dose and Rate
Concerns or Comments†
Labetalol (C)
20 mg IV, then 20–80 mg every 20–30 min,
up to a maximum of 300 mg; or constant
infusion of 1–2 mg/min
5 mg, IV or IM, then 5–10 mg every 20–40
min; or constant infusion of 0.5–10 mg/h
Tablets recommended only; 10–30 mg orally,
repeat in 45 min if needed
Constant infusion of 0.5–10 ␮g/kg/min
Experience in pregnancy less than with hydralazine;
probably less risk for tachycardia and arrhythmia
than with other vasodilators.
Drug of choice according to NHBEP working
group; long experience of safety and efficacy.
Possible interference with labor.
Nifedipine (C)
Relatively contraindicated
nitroprusside (C)‡
Possible cyanide toxicity; agent of last resort.
Hydralazine (C)
IM, intramuscularly; IV, intravenously; NHBEP, National High Blood Pressure Education Program.
Note: Indicated for acute increase of diastolic blood pressure ⱖ105 mm Hg; goal is a gradual reduction to 90 to 100 mm Hg.
* U.S. Food and Drug Administration classification; C indicates that either that studies in animals have revealed adverse effects on the
fetus (teratogenic, embryocidal, or other) or there are no controlled studies in women, or studies in women and animals are not available.
Drugs only should be given if the potential benefits justify the potential risk to the fetus.
Adverse effects for all agents, except as noted, may include headache, flushing, nausea, and tachycardia (primarily caused by precipitous
hypotension and reflex sympathetic activation).
We would classify as category D; there is positive evidence of human fetal risk, but the benefits of use in pregnant women may be
acceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be
used or are ineffective).
Reprinted with permission from Alpern RJ, Hebert SC. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology, 4th ed. San
Diego, California: Academic Press, Elsevier, 2008: 2387.
of mild to moderate hypertension does not prevent superimposed preeclampsia or decrease adverse outcomes and
may even result in smaller fetuses.60 Treatment does appear
to decrease hospitalization of the mother, especially related
to loss of BP control. However, it also appears that many of
the trials reviewed were incomplete and flawed; therefore,
comparing them is difficult because of obvious heterogeneity. Better designed, more definitive trials are needed to
resolve this issue.
Given these limitations, the NHBPEP and American College of Obstetricians and Gynecologists guidelines11,12 accept withholding antihypertensive drugs unless diastolic
levels are above 100 mm Hg (but support treatment at lower
levels if there is evidence of end-organ damage or specific
risk factors such as underlying renal disease). In what may
reflect the vagaries of consensus, they noted “endpoints” for
reinstating treatment include exceeding threshold BPs of
150 to 160 mm Hg systolic and 100 to 110 mm Hg diastolic.
However, subsequent retrospective analyses suggest that
cerebral vascular accidents in women, especially with superimposed preeclampsia, may occur when systolic levels
exceed 150 (and definitely 160) mm Hg and endorse the
more firm suggestion that systolic levels be treated when
they exceed 160 mm Hg.31,61
Antihypertensive Therapy
The reader is referred further to several reviews that
include systematic analysis of trials and detailed discussions
of when and how to treat hypertension during preg-
nancy.13,15,49,62,63 To summarize, clinicians considering the
prescription of antihypertensive drugs to pregnant women
should be aware of several points. There have been only a
few large, randomized multicenter trials. Most studies have
been limited in scope, and many therapies were started after
mid-gestation, when virtually all the risks of provoking
congenital malformations have passed. Further, there are no
rigorous animal testing requirements to be met before human trials are undertaken, including standardized means of
evaluating the drug effect on the fetus’ ability to withstand
hypoxic stress or more complex analyses of morphologic
and physiologic variables in newborn animal models. This
state of affairs should be kept in mind when reviewing the
literature on antihypertensive therapy in pregnancy. Tables
2 and 3 summarize the status of antihypertensive drugs
during gestation, including their pregnancy risk categories
(A to D, through X) as defined by the U.S. Food and Drug
Briefly, the NHBPEP report11 designated the central adrenergic inhibitor methyldopa as the “preferred” drug of
choice based on 20⫹ years of postmarketing surveillance,
several controlled trials, and the longest follow-up (7.5
years) in neonates. Adrenergic blocking agents are associated with an increased incidence of fetal growth restriction
though the effects are minimal, and many clinicians use the
combined beta and adrenergic blocker labetalol.15,62 Theoretically, there may be synergism between magnesium sulfate and calcium-channel blocking agents leading to precipitous decreases in BP and even respiratory arrest, but this
M.D. Lindheimer et al. / Journal of the American Society of Hypertension 2(6) (2008) 484 – 494
1. Ness RB, Roberts JM. Epidemiology of hypertension.
In: Lindheimer MD, Roberts JM, Cunningham FG,
editors. Chesley’s Hypertensive Disorders in Pregnancy, 2nd ed. Stamford, Connecticut: Appleton &
Lange, 1999: 43– 65. (3rd edition revision in press, May
2009, Elsevier).
2. Villar J, Say L, Gulmezoglu AM, Marialdi M, Lindheimer MD, Betran AP, et al. Pre-eclampsia eclampsia: a
health problem for 2000 years. In: Critchly H, MacLean
A, Poston L, Walker J, editors. Pre-eclampsia. London,
England: RCOG Press, 2003: 189 –207.
3. Zandi-Nejad K, Luyckx VA, Brenner BM. Adult hypertension and kidney disease: the role of fetal programming. Hypertension 2006;47:502– 8.
4. Sibai BM. Preeclampsia as a cause of preterm and late
preterm (near-term) births. Semin Perinatol 2006:13:
16 –9.
5. Zhang J, Villar J, Sun W, Meraldi M, Andel-Aleem H,
Mathai M, et al. Blood pressure dynamics during pregnancy and spontaneous preterm labor. Am J Obstet
Gynecol 2007;197:162e1– e6.
6. Harskamp RE, Zeeman GG. Preeclampsia: at risk for
remote cardiovascular disease. Am J Med Sci 2007;
7. Gross CP, Anderson CF, Rowe NR. The relation
between funding by the National Institutes of Health
and the burden of disease. N Engl J Med 1999;340:
8. Davison JM, Lindheimer MD, editors. New developments in preeclampsia. Semin Nephrol 2004;24:537–
9. Moutquin JM, Garner PR, Burrows RF, Rey E, Helewa
ME, Lange IR, et al. Report of the Canadian Hypertension Society Consensus Conference 2. Non-pharmacologic management and prevention of hypertensive disorders of Pregnancy. CMAJ 1997;157:907–19.
10. Brown MA, Hague WM, Higgins J, Lowe S, McCowan
L, Oats J, et al. The detection, investigation and management of hypertension in pregnancy: executive summary.
Aust N Z J Obstet Gynaecol 2000;40:133– 8.
11. Report of the National High Blood Pressure Education
Program Working Group on High Blood in Pregnancy.
Am J Obstet Gynecol 2000;183:S1–22.
12. Diagnosis and management of preeclampsia and
eclampsia. Number 33, January 2002. American College of Obstetricians and Gynecologists (ACOG) 2002;
99:159 – 67.
13. Cunningham FG, Leveno KL, Bloom SL, Hauth JC,
Gilstrap LC, Wenstrom KD. Williams Obstetrics, 22nd
ed. New York, New York: McGraw-Hill Co, 2005:
has not been borne by systematic review.64 Other comments
concerning these agents can be found in Tables 2 and 3.
Both angiotensin-converting enzyme (ACE) inhibitors and
angiotensin receptor blockers should not be prescribed to
pregnant women. Until recently their class D, “black box”
warning focused primarily on their association with fetopathy, including renal failure and death in the neonate. Because the fetal problems occurred related to events in the
last two trimesters, some suggested the drug could be used
through conception or the initial trimester in situations such
as chronic hypertensives where discontinuing the ACE inhibitor or receptor blocker might result in critical difficulties
in reestablishing control with perhaps early pregnancy loss
(eg, a hypertensive class C diabetic receiving the drug at
conception). However, it is now more apparent that these
drugs are also associated with serious fetal anomalies65 and
should not be used early in gestation either.
Information on use of antihypertensive drugs during lactation remains limited. Drugs with high protein binding are
preferred (eg, labetalol or propranolol over atenolol and
metoprolol).11,62 ACE inhibitors are important for treating
proteinuric and diabetic patients and can be quickly be
restarted. Diuretics may decrease breast milk production
and should be withheld.
Other Management Considerations
Obstetrics management, including the current status of
tests to monitor the fetus (eg, electronic fetal heart, monitoring, Doppler assessment of the uteroplacental circulation) is beyond the scope of this article and is discussed in
the obstetric literature, including periodic bulletins issued
by the American College of Obstetricians and Gynecologists.
Remote Prognosis
Results of several large epidemiologic studies demonstrate that women whose pregnancies were complicated by
preeclampsia have more remote cardiovascular and metabolic diseases later in life than women who were normotensive during all of their pregnancies.6,13,15,66 – 68 It also
appears that those women most likely to develop cardiovascular or metabolic diseases have had early preeclampsia
(⬍34 weeks).67 On the other hand, the few studies comparing the remote prognosis of previous preeclamptics to ageand gender-matched populations in the general population
find minimal or no such increases.15 The best interpretation
of these findings is that preeclampsia is a risk marker of
patients predestined to have future cardiovascular or metabolic disease. Such women, therefore, should have more
frequent health check-ups and should be advised that lifestyle and dietary changes may minimize such problems in
the future.
M.D. Lindheimer et al. / Journal of the American Society of Hypertension 2(6) (2008) 484 – 494
adverse maternal or perinatal outcomes. Hypertens
Pregnancy 2007;26:447– 62.
Schiff E, Friedman SA, Kao L, Sibai BM. The importance of urinary protein excretion during conservative
management of severe preeclampsia. Am J Obstet Gynecol 1996;175:1313– 6.
von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy 2003;22:
143– 8.
Mattar F, Sibai BM. Eclampsia. VIII. Risk factors for
maternal morbidity. Am J Obstet Gynecol 2000;182:
Zeeman GG, Vollaard ES, Alexander JM, McIntire
DD, Cunningham FG. “Delta preeclampsia”—a hypertensive encephalopathy in “normotensive” women.
Am J Obstet Gynecol 2007;197:S140.
Hirshfeld-Cytrin J, Lam C, Karumanchi SA, Lindheimer MD. Late postpartum eclampsia: examples and
review. Obstet Gynecol Survey 2006;61:471– 80.
Sibai BM. Diagnosis, controversies, and management
of the syndrome of hemolysis, elevated liver enzymes,
and low platelet count. Obstet Gynecol 2004;103:981–
Hladunewich M, Karumanch SA, Lafayette R. Pathophysiology of the clinical manifestations of preeclampsia. Clin J Am Soc Nephrol 2007;2:543–9.
Lindheimer MD, Umans JG. Explaining and predicting
preeclampsia (editorial). N Engl J Med 2006;355:1056 – 8.
Maynard S, Epstein FH, Karumanchi SA. Preeclampsia
and angiogenic imbalance. Ann Rev Med 2007;59:61–
Li Z, Zhang Y, Ying Ma J, Kapoun AM, Shao Q, Kerr
I, et al. Recombinant vascular endothelial growth factor
121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia. Hypertension 2007;
50:686 –92.
Dechend R, Homuth V, Wallukat G, Müller DN,
Krause M, Dudenhausen J, et al. Agonistic antibodies
directed at the angiotensin II, AT1 receptor in preeclampsia. J Soc Gynecol Invest 2006;13:79 – 86.
Xia Y, Ramin SM, Kellems RE. Potential roles of
angiotensin receptor-activating autoantibody in the
pathophysiology of preeclampsia. Hypertension 2007;
50:269 –75.
Conrad KP, Lindheimer MD. Renal and cardiovascular alterations. In: Lindheimer MD, Roberts JM,
Cunningham FG, editors. Chesley’s Hypertensive
Disorders in Pregnancy, 2nd ed. Stamford, Connecticut: Appleton & Lange, 1999:263–326. (3rd edition
revision in press, May 2009, Elsevier).
McMaster MT, Zhou Y, Fisher SJ. Abnormal placentation and the syndrome of preeclampsia. Semin Nephrol 2004;24:540 –7.
Sheehan HL, Lynch JP. The pathology of toxemia.
Baltimore, Maryland: Wilkins and Wilkins, 1973.
14. Hibbard JU, Shroff SG, Lang RM. Cardiovascular
changes in preeclampsia. Semin Nephrol 2004;24:580 –7.
15. Lindheimer MD, Conrad KP, Karumanchi SA. Renal
physiology and disease in pregnancy. In: Alpern RJ,
Hebert SC, editors. Seldin and Giebisch’s The Kidney;
Physiology and Pathophysiology, 4th ed. San Diego,
California: Academic Press, Elsevier, 2008:2339 –98.
16. Friedman EA, Neff RK. Pregnancy, Hypertension: A
Systematic Evaluation of Clinical Diagnostic Criteria.
Littleton, Massachusetts: PSG Publishing, 1977.
17. Page EW, Christianson RE. The mean impact of mean
arterial pressure in the middle trimester on the outcome
of pregnancy. Am J Obstet Gynecol 1976;125:740 – 6.
18. Sibai BM, Caritis SN, Thon E, Klebanoff M, McNellis
D, Rocco L, et al. Prevention of preeclampsia with
low-dose aspirin in healthy nulliparous women. The
National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.
N Engl J Med 1993;39:1213– 8.
19. Shennan AH, Waugh J. The measurement of blood
pressure and proteinuria in pregnancy. In: Critchly H,
MacLean A, Poston L, Walker J, editors. Pre-eclampsia. London, England: RCOG Press, 2003:305–24.
20. August P, Lindheimer M. Chronic hypertension and
pregnancy. In: Lindheimer MD, Roberts JM, Cunningham FG, editors. Chesley’s Hypertensive Disorders in
Pregnancy, 2nd ed. Stamford, Connecticut: Appleton &
Lange, 1999:605–33.
21. Dugas G, Fuller J, Singh S, Watson J. Pheochromocytoma and pregnancy: a case report and review of anesthetic management. Can J Anaesth 2004;51:134 – 8.
22. Blanco C, Maqueda E, Rubiio JA, Rodriquez A. Cushing’s syndrome during pregnancy secondary to adrenal
adenoma: metyrapone treatment and laparoscopic adrenalectomy. J Endocrinol Invest 2006;29:164 –7.
23. Lindheimer M, Richardson DA, Ehrlich EN, Katz AI.
Potassium homeostasis in pregnancy. J Reprod Med
24. Fisher KA, Luger A, Spargo BH, Lindheimer MD.
Hypertension in pregnancy: clinical pathological correlations and remote prognosia. Medicine (Baltimore)
25. Villar J, Carroli G, Wojdyla D, Abalos E, Giordano D,
Ba’aqeel H, et al. Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions? Am J Obstet Gynecol 2006;194:
26. Geller DS, Fahri A, Pinkerton N, Fradley M, Moritz M,
Spitzer A, et al. Activating mineralocorticoid receptor
mutation in hypertension exacerbated by pregnancy.
Science 2000;289:119 –23.
27. Menzies J, Magee LA, MacNab YC, Ansermino JM, Li
J, Douglas MJ, et al. Current CHS and NHBPEP criteria for severe preeclampsia do not uniformly predict
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55. von Dadelszen P, Menzies J, Gilgoff S, Xie F, Douglas
MJ, Sawchuck D, et al. Evidence-based management
for preeclampsia. Front Biosci 2007;12:2876 – 89.
56. Sibai BM, Barton JR. Expectant management of severe
preeclampsia remote from term: patient selection, treatment, and delivery indications Am J Obstet Gynecol
57. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing preeclampsia and its
complications. Cochrane Database Syst Rev 2007;2:
58. Sibai BH. Magnesium sulfate prophylaxis in preeclampsia: lessons learned from recent trials. Am J
Obstet Gynecol 2004;190:1520 – 6.
59. Gilbert WM, Young AL, Danielson B. Pregnancy outcome in women with chronic hypertension: a population based study. J Reprod Med 2007;52:1046 –51.
60. von Dadelszen P, Magee LA. Fall in mean arterial
pressure and fetal growth restriction in pregnancy hypertension: an updated metaregression analysis. J Obstet Gynaecol Can 2002:24:941–5.
61. Martin JN Jr, Thigpen BD, Moore RC, Rose CH, Cushman J, May W. Stroke and severe preeclampsia, and
eclampsia: a paradigm shift focusing on systolic blood
pressure. Obstet Gynecol 2005;246 –54.
62. Podymow T, August P, Umans JG. Antihypertensive
therapy in pregnancy. Semin Nephrol 2004;24:616 –25.
63. Abalos E, Duley L, Steyn DW, Henderson-Smart DJ.
Antihypertensive drug therapy for mild to moderate
hypertension during pregnancy. Review. Cochrane Database Syst Rev 2007;1:CD002252.
64. Magee LA, Miremadi S, Li J, Ensom MH, Carleton B,
Côtè AM, et al. Therapy with both magnesium sulfate
and nifedipine does not increase the risk of serious
magnesium-related maternal side effects in women
with preeclampsia. Am J Obstet Gynecol 2005;193:
153– 63.
65. Cooper WO, Hemandez-Diaz S, Arbogast PD, Dudley
JA, Dyer S, Gideon PS, et al. Major congenital anomalies after first-trimester exposure to ACE inhibitors.
N Engl J Med 2006;354:2443–51.
66. Jonsdottir LS, Arngrimsson R, Geirsson RT, Sigvaldason
H, Sigfússon N. Death rates from ischemic heart disease in
women with a history of hypertension in pregnancy. Acta
Obstet Gynecol Scand 1995;74:772– 6.
67. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long-term
mortality of mothers and fathers after preeclampsia:
population-based cohort study. BMJ 2001;323:1213–7.
68. Funai EF, Friedlander Y, Paltiel O, Tiram E, Xue X,
Deutsch L, et al. Long-term mortality after preeclampsia. Epidemiology 2005;16:206 –15.
43. Zeeman GG, Hatab MR, Twickler DM. Increased cerebral blood flow in preeclampsia with magnetic resonance imaging. Am J Obstet Gynecol 2004;191:
44. Cipolla MJ. Cerebrovascular function in pregnancy and
eclampsia. Hypertension 2007;50:14 –24.
45. Zeeman GG, Fleckenstein GL, Twinckler DM, Cunningham FG. Cerebral infarction in preeclampsia. Am J
Obstet Gynecol 2004;190:714 –20.
46. Baker PN, Cunningham FG. Platelet and coagulation
abnormalities. In: Lindheimer MD, Roberts JM, Cunningham FG, editors. Chesley’s Hypertensive Disorders in Pregnancy, 2nd ed. Stamford, Connecticut:
Appleton & Lange, 1999:349 –75. (3rd edition revision
in press, May 2009, Elsevier).
47. Dani R, Mendes GS, Medeiros Jde L, Péret FJ, Nunes
A. Study of the liver changes occurring in preeclampsia
and their possible pathogenetic connection with acute
fatty liver of pregnancy. Am J Gastroenterol 1996;91:
292– 4.
48. Conde-Agudelo A, Villar J, Lindheimer MD. WHO
systematic review of screening tests for prediction of
preeclampsia. Obstet Gynecol 2004;104:1367–914.
49. Widmer M, Villar J, Benigni A, Conde-Agudelo A,
Karumanchi SA, Lindheimer M. Mapping the theories
of preeclampsia and the role of angiogenic factors.
Obstet Gynecol 2007:109:168 – 80.
50. Villar J, Abalos E, Nardin JM, Merialdi M, Carroli G.
Strategies to prevent and treat preeclampsia. Evidence
from randomized controlled trials. Semin Nephrol
51. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA,
PARIS Collaborative Group. Antiplatelet agents for
prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet 2007;369:1765– 6.
52. Villar J, Abdel-Aleem H, Merialdi M, Mathai M, Ali
MM, Zavaleta N, et al. World Health Organization
randomized trial of calcium supplementation among
low calcium intake pregnant women. Am J Obstet Gynecol 2006;194:639 – 49.
53. Poston L, Briley A, Seed P, Kelly F, Shennan A, the
Vitamins in Pre-eclampsia (VIP) Trial Consortium. Vitamin C and vitamin E in pregnant women at risk for
pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006;367:1145–54.
54. Rumbold A, Crowther C, Haslam R, Dekker G, Robinson J. Vitamins C and E and the risks of preeclampsia
and perinatal complications. N Engl J Med 2006;354:
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Journal of the American Society of Hypertension 4(1) (2010) 42–50
ASH Position Article
Combination therapy in hypertension
Alan H. Gradman, MDa,*, Jan N. Basile, MDb, Barry L. Carter, PharmDc, and
George L. Bakris, MDd,
on behalf of the American Society of Hypertension Writing Group
The Western Pennsylvania Hospital, Pittsburgh, Pennsylvania and Temple University School of Medicine, Philadelphia, PA, USA;
Ralph H. Johnson VA Medical Center, Medical University of South Carolina, Charleston, SC, USA;
Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA; and
The University of Chicago Pritzker School of Medicine, Chicago, IL, USA
Manuscript received February 5, 2010 and accepted February 5, 2010
The goal of antihypertensive therapy is to abolish the risks associated with blood pressure (BP) elevation without adversely
affecting quality of life. Drug selection is based on efficacy in lowering BP and in reducing cardiovascular (CV) end points
including stroke, myocardial infarction, and heart failure. Although the choice of initial drug therapy exerts some effect on
long-term outcomes, it is evident that BP reduction per se is the primary determinant of CV risk reduction. Available data suggest
that at least 75% of patients will require combination therapy to achieve contemporary BP targets, and increasing emphasis is
being placed on the practical tasks involved in consistently achieving and maintaining goal BP in clinical practice. It is within this
context that the American Society of Hypertension presents this Position Paper on Combination Therapy for Hypertension. It will
address the scientific basis of combination therapy, present the pharmacologic rationale for choosing specific drug combinations,
and review patient selection criteria for initial and secondary use. The advantages and disadvantages of single pill (fixed) drug
combinations, and the implications of recent clinical trials involving specific combination strategies will also be discussed. J Am
Soc Hypertens 2010;4(1):42–50. Ó 2010 American Society of Hypertension. All rights reserved.
Keywords: Hypertension; combination therapy; drug therapy; angiotensin converting enzyme inhibitor; angiotensin receptor blocker; beta blockers diuretic;
calcium channel blocker.
The goal of antihypertensive therapy is to abolish the risks
associated with blood pressure (BP) elevation without
adversely affecting quality of life. Epidemiologic studies
and clinical trials have been used to define individual risk
and set appropriate BP targets,1–3 recognizing that these
targets reflect expert consensus based on available data and
are subject to revision as additional evidence is obtained.4
Drug selection is based on efficacy in lowering BP and in
reducing cardiovascular (CV) end points including stroke,
myocardial infarction, and heart failure. Although the choice
of initial drug therapy exerts some effect on long-term
outcomes, it is evident that BP reduction per se is the primary
determinant of CV risk reduction. As a result, there has been
*Corresponding author: Dr. Alan H. Gradman, The Western
Pennsylvania Hospital, Department of Medicine, 4800 Friendship
Avenue, Pittsburgh, PA 15224. Tel: 412-721-4915.
E-mail: [email protected]
a progressive lowering of BP targets in large segments of the
hypertensive population, including diabetics and patients
with established renal or vascular disease.1–3,5 At the same
time, increasing emphasis is being placed on the practical
tasks involved in consistently achieving and maintaining
goal BP in clinical practice.
It is within this context that the American Society of
Hypertension presents this Position Paper on Combination
Therapy for Hypertension. It will address the scientific
basis of combination therapy, present the pharmacologic
rationale for choosing specific drug combinations, and
review patient selection criteria for initial and secondary
use. The advantages and disadvantages of single pill (fixed)
drug combinations (SPC) and the implications of recent
clinical trials involving specific combination strategies
will also be discussed.
Combination Therapy: A Practical Necessity
The ability to maintain constant or near-constant BP in
response to various stressors is central to homeostasis, and
1933-1711/10/$ – see front matter Ó 2010 American Society of Hypertension. All rights reserved.
A.H. Gradman et al. / Journal of the American Society of Hypertension 4(1) (2010) 42–50
patients are exposed to multiple drugs and then treated with
the most effective agent.12 In the Strategies in Treatment of
Hypertension study, treatment initiated with a low-dose
combination was compared with a monotherapy arm in
which patients were first treated with a b-blocker but could
be switched to an ACE inhibitor or a CCB if BP remained
>140/90 mm Hg. At the end of 9 months, a significantly
higher percentage of patients randomized to the low-dose
combination achieved target BP compared with those
receiving sequential monotherapy (62% vs. 49%, P ¼ .02).13
The aggregate of available data suggests that at least 75%
of patients will require combination therapy to achieve
contemporary BP targets. This estimate reflects the results
of previous studies, the lower BP targets now in place for
large segments of the hypertensive population, and the
rapidly increasing prevalence of obesity. The latter is important as the presence of obesity further elevates pretreatment
BP and increases the magnitude of BP reduction needed to
achieve therapeutic targets.14
The importance of achieving goal BP in individual patients
cannot be overemphasized. In major clinical trials, small
differences in on-treatment BP frequently translate into major
differences in clinical event rates. Recent data also suggest
that inadequate BP control is itself an independent risk factor
for the development of diabetes in hypertensive patients.15
the human organism has redundant physiologic mechanisms
for regulating arterial pressure. BP is determined primarily
by three factors: renal sodium excretion and resultant plasma
and total body volume, cardiac performance, and vascular
tone.6 These factors control intravascular volume, cardiac
output, and systemic vascular resistance, which are the immediate hemodynamic determinants of BP. Both the sympathetic
nervous system and the renin-angiotensin-aldosterone system
(RAAS) are intimately involved in adjusting these parameters
on a real-time basis. In addition, genetic makeup, diet, and
environmental factors influence BP in individual patients.
Although it is occasionally possible to identify a specific
cause for hypertension in some patients, BP elevation is
usually multifactorial, making it very difficult, if not impossible, to normalize pressure by interfering with only a single
pressor mechanism. In addition, drug therapy directed at any
one component routinely evokes compensatory (counterregulatory) responses that reduce the magnitude of response,
even if it was accurately directed at the predominant pathophysiologic mechanism. As a consequence, limited BP
reduction is seen with all available antihypertensive agents.
In a recent meta-analysis by Law et al of 354 randomized,
double-blind trials, the mean placebo-corrected reduction
in BP with monotherapy was only 9.1/5.5 mm Hg.7 There
was little difference in this regard between a diuretic,
b-blocker, angiotensin-converting enzyme (ACE) inhibitor,
angiotensin receptor blocker (ARB), or calcium channel
blocker (CCB). Similar results were found in the Treatment
of Mild Hypertension study, in which comparable BP reduction was observed after long-term treatment with a diuretic,
b-blocker, CCB, a-blocker, and ACE inhibitor.8
Clinical trials document that achieving BP targets is usually
not possible with a single agent. In the Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial,
only 26% of patients achieved goal BP with monotherapy—
despite the fact that the target BP for diabetics (36% of
the patient population) was <140/90 mm Hg rather than the
<130/80 mm Hg mandated by current guidelines.9 In the
Hypertension Optimal Treatment trial, 33% of patients
achieved their (diastolic only) BP target with monotherapy,
45% required two drugs, and 22% needed three or more
agents.10 Systolic BP at the end of the study averaged 141
mm Hg, indicating that even a higher percentage would have
required combination therapy according to current treatment
standards. In the Losartan Intervention for Endpoints trial, in
which treatment to goal (<140/90 mm Hg) was aggressively
pursued in patients with left ventricular hypertrophy and
a mean baseline BP of 175/98 mm Hg, more than 90% required
at least two antihypertensive agents.11
The importance of blocking multiple physiologic pathways is underscored by studies using a treatment strategy
known as ‘‘sequential monotherapy.’’ This approach is based
on the observation that BP response to different antihypertensive medications is often quite variable, and BP control
should be more readily achieved with monotherapy if
Combination Therapy: Theoretical
Rational combination therapy is based on the deliberate
coadministration of two or more carefully selected antihypertensive agents. Inclusion of drugs known to reduce the
long-term incidence of CV end points is highly preferred.
A fundamental requirement of any combination is evidence
that it lowers BP to a greater degree compared with monotherapy with its individual components. This is achieved
by combining agents that either interfere with distinctly
different pressor mechanisms or effectively block counterregulatory responses. Combining two drugs may result in
partial or complete additivity of their BP-lowering effects,
depending on the degree to which their pharmacologic
effects are distinct and complimentary. Fully additive
combinations are more effective in terms of BP reduction.
In general, combining drugs from complementary classes
is approximately five times more effective in lowering BP
than increasing the dose of one drug.16 Another important
requirement of a combination is pharmacokinetic compatibility (ie, combined drug administration results in smooth
and continuous BP reduction throughout the dosing
interval).17 These principles apply regardless of whether
agents are included in an SPC or are coadministered as
separate drugs.
A.H. Gradman et al. / Journal of the American Society of Hypertension 4(1) (2010) 42–50
Specific Drug Combinations
Improving the overall tolerability of treatment is a key
element in designing rational drug combinations. This
beneficial effect will occur whenever side effects associated
with a particular agent are neutralized by the pharmacologic properties of an added drug.17 Because most antihypertensive agents produce dose-dependent side effects,
high-dose monotherapy may lead to adverse events. In
this circumstance, a lower dose of the initial agent in
combination with another antihypertensive may be preferable to minimize dose-dependent side effects even if no
additional BP reduction is achieved. An example is the
use of a low-dose combination of an ACE inhibitor and
a dihydropyridine CCB in a patient who develops edema
at a higher CCB dose. In this instance, reducing the CCB
dose and adding an ACE inhibitor will produce comparable
BP reduction, but will generally do so without the side
effects previously observed.18
There are seven major classes of antihypertensive drugs
and multiple members of each class; therefore, the number
of possible combinations is quite large. In this position
paper, two-drug combinations involving classes of pharmacologic agents that reduce CV end points (diuretics, CCBs,
ACE inhibitors, ARBs, b-blockers) are emphasized.
Combinations of three or more drugs are not reviewed.
Specific combinations are designated as preferred or
acceptable based on the considerations outlined previously.
Combinations that are less effective on the basis of efficacy,
safety, or tolerability concerns are also identified.
The combination of an ACE inhibitor, ARB, or direct renin
inhibitor with a low-dose, thiazide-type diuretic results in
fully additive BP reduction.22–26 Diuretics initially reduce
intravascular volume and activate the RAAS, leading to
vasoconstriction as well as salt and water retention. In the
presence of a RAAS inhibitor, this counterregulatory
response is attenuated. Addition of a RAAS inhibitor to a
thiazide-type diuretic also improves its safety profile by
ameliorating diuretic-induced hypokalemia,27 but can result
in hyperkalemia in susceptible patients. Based on their safety,
efficacy, and favorable performance in long-term trials,
combinations of an ACE inhibitor or an ARB with a lowdose diuretic are classified as preferred. Most FDCs containing a diuretic use hydrochlorthiazide (HCTZ). Because
chlorthalidone is more effective than other diuretics in
reducing BP over 24 hours28 and was the agent used in all
but one large US-based hypertension outcome trial, some
authorities favor its use over HCTZ. Because it is not
currently aligned in any SPC with an ACE inhibitor or
ARB, it can be administered as a separate agent.
Long-term adherence to treatment is necessary to control
BP, and combination regimens can facilitate this objective,
both in reducing the number of medications and the
frequency of dosing required. A recent study of w85,000
patients from Kaiser Permanente found that adherence was
inversely related to the number of medications prescribed.
In this study, antihypertensive medication adherence levels
were 77.2%, 69.7%, 62.9%, and 55% in subjects receiving
one-, two-, three-, or four-drug regimens.19 Other studies
have found that adherence drops even more dramatically
with increasing number of doses taken per day from 71%
with once-daily dosing to 61%, 50%, and 31% with two,
three, or four daily doses of antihypertensive medication.20
In many patients, SPCs promote adherence by reducing pill
burden and simplifying the treatment regimen. In a metaanalysis of nine studies comparing administration of SPCs
or their separate components, the adherence rate was
improved by 26% in patients receiving SPCs.21
It should be emphasized that simplification of the treatment regimen is only one strategy for improving adherence.
For many patients, cost is a critical issue. Branded combinations that are not available generically are often more
expensive and can, in some cases, result in significant
copays that adversely affect medication adherence. It should
be noted that many SPCs that combine an ACE inhibitor
with a diuretic are generic, as is one ACE inhibitor/
CCB combination. Physicians should be aware of these
generic preparations and use them when necessary. They
should not assume that an SPC improves adherence in
every situation, particularly if its use increases direct
patient expenditure or does not significantly reduce pill
burden because the patient is receiving multiple other
RAAS Inhibitor þ Diuretic
RAAS Inhibitor þ CCB
The combination of an ACE inhibitor or ARB with a CCB
results in fully additive BP reduction.29–31 Addition of either
of these two RAAS inhibitors significantly improves the
tolerability profile of the CCB. Through their antisympathetic effects, RAAS inhibitors blunt the increase in heart
rate that may accompany treatment with a dihydropyridinetype CCB. In addition, RAAS inhibitors partially neutralize
the peripheral edema, which is a dose-limiting side effect
of these CCBs.32 The cause of the edema is believed to be
arteriolar dilation, resulting in an increased pressure gradient
across capillary membranes in dependent portions of the
body. RAAS blockers are thought to counteract this effect
through venodilation.
The Avoiding Cardiovascular events through Combination therapy in Patients Living with Systolic Hypertension
trial tested whether initial fixed-dose combination therapy
A.H. Gradman et al. / Journal of the American Society of Hypertension 4(1) (2010) 42–50
Renin Inhibitor þ ARBs
The combination of a diuretic and a CCB results in
partially additive BP reduction.37,38 Presumably, this partial
effect reflects overlap in the pharmacologic properties of
the two drugs. CCBs increase renal sodium excretion, albeit
not to the same extent as diuretics. Moreover, long-term treatment with both classes is associated with vasodilation, given
that volume depletion does not occur with diuretics. From an
endpoint perspective, this combination performed well in the
Valsartan Antihypertensive Long-term Use Evaluation trial
in which HCTZ was added as a second step in patients
randomized to amlodipine.39 As opposed to ACE inhibitor/
CCB or ARB/CCB combinations, the CCB þ diuretic has
no favorable effect on either drug’s side effect profile. These
combinations are classified as acceptable.
Thiazide Diuretics þ Potassium-sparing
Hypokalemia is an extremely important dose-related side
effect of thiazide diuretics. By attenuating hypokalemia,
the combination of HCTZ with a potassium-sparing diuretic
such as triamterene, amiloride, or spironolactone improves
its safety profile.48 Because of the risk of hypokalemia that
can lead to cardiac arrhythmias, and sudden death, HCTZ
50 mg and chlorthalidone 25 mg should generally be used
in combination with a potassium-sparing agent (or an inhibitor of the RAAS). Given the latest data demonstrating the
importance of aldosterone blockade in obese patients and
the efficacy of aldosterone blockade in helping achieve BP
goals, the spironolactone/HCTZ combination is particularly
well-suited in such individuals.49 The addition of amiloride
to HCTZ reduces hypokalemia and results in variable BP
reduction.50,51 These combinations are classified as acceptable in people with relatively well-preserved kidney function
(ie, estimated glomerular filtration rate >50 mL/min/1.73
m2). At glomerular filtration rate levels below this, the risk
for hyperkalemia increases and the diuretic efficacy of
HCTZ starts to diminish.52
The combination of a renin inhibitor with an ARB
produces partially additive BP reduction and is welltolerated. In a study in which maximum approved doses of
valsartan and aliskiren were combined, a 30% additional
BP response was observed compared with either monotherapy.36 The side effect profile of this acceptable combination
was comparable with placebo. There are no cardiovascular
outcome data with this combination to date.
CCBs þ Diuretics
diuretics, and their combination results in fully additive BP
reduction.44–46 Addition of diuretics also improves the effectiveness of b-blockers in blacks and others with low renin
hypertension.47 These combinations are classified as acceptable, recognizing that their use is associated with increased
risk of glucose intolerance, fatigue, and sexual dysfunction.
with an ACE inhibitor and CCB differs from initial
fixed-dose combination therapy with an ACE inhibitor
and diuretic on clinical outcomes in high-risk hypertensive
patients. Despite comparable BP reduction, the ACE
inhibitor/CCB combination reduced the combined end
point of cardiovascular death, myocardial infarction, and
stroke by 20% compared with the ACE inhibitor/diuretic
combination.33 Of note, 60% of patients were diabetic,
and a large percentage had evidence of underlying ischemic
heart disease.34 These results suggest the superiority of
a CCB over a diuretic when used in conjunction with
a RAAS blocker in this high-risk population. ACE inhibitor/CCB combinations are classified as preferred. In view
of end point studies demonstrating comparability between
ACE inhibitors and ARBs, ARB/CCB combinations are
considered to be equivalent.35
b-Blockers þ Diuretics
Although b-blockers reduce CV end points in placebocontrolled trials, meta-analyses (based primarily on the
performance of atenolol) suggest that they are less effective
than diuretics, ACE inhibitors, ARBs, and CCBs.40–42 The
antihypertensive effects of b-blockers are mediated through
reduction in cardiac output and suppression of renin release.43
As with the ACE inhibitors and ARBs, b-blockers attenuate
the RAAS activation that accompanies the use of thiazide
CCBs þ b-Blockers
The pharmacologic effects of these two drug classes are
complementary, and their combination results in additive
BP reduction. In one study, a low-dose combination of
felodipine ER and metoprolol ER produced BP reduction
comparable to maximum doses of each agent with an incidence of edema similar to placebo.53,54 The combination of
a b-blocker and a dihydropyridine CCB is acceptable.
b-blockers should not generally be combined with nondihydropyridine CCBs such as verapamil or diltiazem because
their additive effects on heart rate and A-V conduction
may result in severe bradycardia or heart block.
Less Effective Combinations
ACE Inhibitors þ ARBs
Although sometimes useful for proteinuria reduction and
in the treatment of symptomatic patients with heart failure,
the combination of an ACE inhibitor and an ARB is not
recommended for the treatment of hypertension. ACE/
ARB combinations produce little additional BP reduction
compared with monotherapy with either agent alone. In
the Ongoing Telmisartan Alone and in Combination with
A.H. Gradman et al. / Journal of the American Society of Hypertension 4(1) (2010) 42–50
Ramipril Global Endpoint Trial, patients receiving the ACE
inhibitor/ARB combination showed no improvement in
cardiovascular end points despite additional BP reduction
averaging 2.4/1.4 mm Hg.35 There were also more side
effects with the combination than with individual agents.
These combinations are classified as less effective.
RAAS Inhibitor þ b-Blocker
b-Blockers þ Centrally Acting Agents
These drug classes are both cardioprotective and are
frequently coadministered to patients with coronary heart
disease or heart failure. When these agents are combined,
however, they produce little additional BP reduction
compared with either monotherapy.55 For this reason, they
constitute a less effective combination when BP reduction
is the principal goal. They can, however, be used together
in patients with coronary artery disease or heart failure
when outcome improvement is the primary objective.
b-blockers and centrally acting agent (eg, clonidine,
a-methyldopa) interfere with the sympathetic nervous
system. The degree to which they produce additive BP reduction has not been studied. When used together, their combination may result in severe bradycardia or heart block. In
addition, when discontinued abruptly, patients receiving
these drugs in combination may exhibit severe rebound
hypertension.56 For this reason, they constitute a less effective combination.
Clinical Application
Patient Selection: Initial Therapy
Because most patients with hypertension will require two
to three drugs to achieve BP control, the pivotal questions
for initial therapy are as follows.
Should treatment be started with monotherapy or
a combination?
If two drugs are initiated, should they be administered
as single entities or an SPC?
Although there is limited scientific evidence to answer
these questions definitively, several considerations support
the use of initial combination therapy in most patients with
hypertension. Initiation of multiple drugs targets multiple
physiologic pathways, making it more likely that those
making a significant contribution to BP elevation will be
inhibited. By beginning with combination therapy, counterregulatory responses will be reduced. The result is an
increase in the percentage of responders as well as increased
magnitude of response in any population of hypertensive
Recent studies also suggest an important correlation
between the time taken to achieve goal BP and clinical
outcome. In the Valsartan Antihypertensive Long-term
Use Evaluation trial, a post hoc analysis indicated that
subjects who reached target BP within 6 months of entering
the protocol demonstrated substantially better outcomes
throughout the 5-year duration of the study, regardless of
assigned treatment.57 Likewise, in the International Verapamil SR-Trandolapril study, lower CV risk was documented
in patients who spent a larger fraction of the time with BP
<140/90 mm Hg.58,59 It is therefore prudent to adopt
therapeutic approaches designed to achieve goal BP within
several months whenever possible.
Several studies have documented that BP control is achieved
more rapidly using an initial combination strategy. Weir et al
compared the time to achieve goal BP with fixed doses of the
ARB, valsartan, alone and in combination with HCTZ in
a meta-analysis of nine randomized trials that included subjects
with either stage 1 or stage 2 hypertension. After 8 weeks of
treatment, 48% of patients begun on monotherapy with the
usual starting dose of valsartan achieved their Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC)-7 target compared with
75% begun on a combination of HCTZ with the same dose
of valsartan.60 In the Avoiding Cardiovascular events through
Combination therapy in Patients Living with Systolic Hypertension study, the first major end point trial in which treatment
was initiated with an SPC, BP was reduced to <140/90 mm Hg
in 73% of patients after 6 months.61 The Simplified Treatment
Intervention to Control Hypertension study compared the
effectiveness of a treatment algorithm using an initial SPC
(ACEI/HCTZ or ARB/HCTZ) to a guideline-based approach
that included initial monotherapy in 45 Canadian family practices. In this ‘‘real-world’’study, the proportion of subjects who
achieved target BP within 6 months was 65% in those initiated
with the SPC compared with 53% receiving guideline-based
treatment. Patients initiated on the SPC experienced no additional side effects.62
Current guidelines suggest that two drugs be used for
initial therapy if there is a 20/10 mm Hg elevation in BP
above goal (BP is >160/100 mm Hg for patients with uncomplicated hypertension or >150/90 for those with diabetes and
other comorbid conditions).1–3 For patients with stage 1
hypertension, it is often reasonable to start with monotherapy. Recent data, however, suggest that the advantages of
initial combination treatment may extend to stage 1 hypertension. In the meta-analysis by Weir, the magnitude of effect
in terms of time-specific achievement of goal BP was greater
in the stage 1 compared with the stage 2 subgroup. Among
patients who were stage 1, 72% achieved their JNC-7 target
by week 8 if initiated on valsartan 160 mg monotherapy vs.
92% who received initial therapy with the same dose of
valsartan in combination with HCTZ.60 With regard to
tolerability, the percentage of patients complaining of dizziness was higher in the combination treatment group, but the
number who discontinued therapy from adverse events was
A.H. Gradman et al. / Journal of the American Society of Hypertension 4(1) (2010) 42–50
generally be avoided or used with caution. The choice of
specific combinations will be dictated by individual patient
considerations including demographics, comorbid conditions, response to previous treatments, and cost, as well
as physician preference. The goal is always cost-effective,
long-term treatment which controls BP using agents that
are safe, effective, and well-tolerated.
Drug Combinations in Hypertension: Recommendations
Summary Recommendations
Use combination therapy routinely to achieve BP
ARB, angiotensin receptor blocker; ACE, angiotensinconverting enzyme; CCB, calcium channel blocker.
* Single pill combinations available in the United States.
Initiate combination therapy routinely in patients who
require 20/10 mm Hg BP reduction to achieve target
Initiate combination therapy in stage 1 patients (at the
physician’s discretion), especially when the second
agent will improve the side effect profile of initial
Use SPCs rather than separate individual agents in
circumstances where convenience outweighs other
Use only preferred or acceptable two-drug combinations
ACE inhibitor/diuretic*
ACE inhibitor/CCB*
CCB (dihydropyridine)/b-blocker
Renin inhibitor/diuretic*
Renin inhibitor/ARB*
Thiazide diuretics/Kþ sparing diuretics*
Less effective
ACE inhibitor/ARB
ACE inhibitor/b-blocker
CCB (nondihydropyridine)/b-blocker
Centrally acting agent/b-blocker
Single pill combinations may be used: as initial treatment
in a patient in whom multidrug therapy is likely to be needed,
as the ‘‘second step’’ in a patient partially controlled on
monotherapy, or as a substitute for independently titrated
doses of individual components. Convenience is the major
advantage of using an SPC. It is easier for the patient to
comply with a regimen that includes fewer pills.63 In addition, it takes less time for a physician to achieve BP control
in a group of patients using a combination that is known
to be safe, effective, and well-tolerated.62,64 On the other
hand, SPCs may significantly increase the cost to the patient
compared with adding individual generic drugs and may
affect the pharmacokinetics of administered agents. The
same or better control rates and medication costs as SPCs
can be achieved through the use of a labor intensive,
knowledge-based approach. For example, in the Collaborative Management of Hypertension study, a physician/
pharmacist team achieved an 89% BP control rate within 9
months using such an approach.65 Although some form of
combination treatment is a necessity, similar treatment results
are achievable with or without the routine use of SPCs. The
choice can be made based on the individual practice setting
and the resources available to both patient and physician.
Combination Therapy: Partially Treated Patients
In patients who are taking antihypertensive therapy but
do not have their BP controlled, additional treatment is
indicated. The selection of specific combinations should
be made from those that are listed as preferred or acceptable in the Table; less effective combinations should
This article was reviewed by Raymond R. Townsend,
MD, and Matthew R. Weir, MD.
The American Society of Hypertension Writing Group
Steering Committee: Barry J. Materson, MD, MBA, Chair;
Henry R Black, MD; Joseph L. Izzo, Jr., MD; Suzanne
Oparil, MD; and Michael A. Weber, MD.
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Journal of the American Society of Hypertension 5(5) (2011) 425–432
ASH Position Paper
Management of hypertension in the transplant patient
Matthew R. Weir, MDa,* and Daniel J. Salzberg, MDa
Division of Nephrology, Department of Medicine, University of Maryland, School of Medicine, Baltimore, MD
Manuscript Accepted July 7, 2011
Statement of the Problem
The development of hypertension after kidney transplantation is common.1,2 Hypertension, defined as a blood pressure greater than 140/90 mm Hg, is associated with an
increased risk for both acute rejection and lower graft and
patient survival.3 The pathogenesis is multifactorial, and
optimal therapy has yet to be clearly defined.
Despite the restoration of kidney function and improvement of intravascular volume control with kidney transplantation, the problems of posttransplant hypertension
remain substantial. The incidence of posttransplant hypertension is variable, but considerable. Most studies report
incidence rates between 60% and 80%.4,5 In one crosssectional study of 409 stable kidney allograft recipients,
the incidence of hypertension was 77.3%, with hypertension defined as a blood pressure greater than 150/90 mm
Hg.4 In this analysis, the majority of patients (68.9%)
required multiple antihypertensive drugs. Similarly, in pediatric kidney transplant recipients, a recent database analysis
described the incidence of posttransplant hypertension at
74%.5 National guidelines6 define hypertension as greater
than 140/90 mm Hg, which is also the typical definition
used in most studies of patients with kidney transplants.
However, national guidelines also recommend treatment
goals lower than 130/80 mm Hg for the general population
with diabetes or estimated glomerular filtration rate (GFR)
below 60 mL/min/1.73 m2.6 Thus, the true prevalence of
posttransplant hypertension using this reference range is
likely in excess of 95%.
Given the fact that transplant centers rarely report their
data on achieved levels of blood pressure control, coupled
with the fact that there is decreased exposure time to their
transplant center physicians (as their patients return to their
primary nephrologist or primary care physicians), the
current status of control rates of hypertension is unknown.
This lack of data is concerning, as a major cause of
posttransplant hypertension is related to calcineurin inhibitor (i.e., cyclosporine and tacrolimus) and corticosteroid
use. The calcineurin inhibitors are known to be directly
nephrotoxic. They decrease renal blood flow and elevate
blood pressure through multiple mechanisms including
stimulation of endothelin production, or the sympathetic
and renin angiotensin systems (RAS). Corticosteroids
enhance sodium and water retention.
Treatment is often a challenge. The majority of kidney
transplant patients are on complex multidrug regimens,
which can be associated with reduced medication adherence. Thus, the likelihood of transplant patients achieving
a blood pressure at a recommended goal of less than 130/
80 mm Hg, for the general population with diabetes or
reduced GFR, is problematic.
Complicating this attempt to achieve ‘‘adequate’’ blood
pressure control are significant gaps in our knowledge typified by the following questions: What are optimal antihypertensive treatment strategies with diabetes or chronic
kidney disease? Specifically, do kidney transplant recipients derive the same cardiovascular and kidney disease
risk reduction benefit with drugs that block the reninangiotensin system, such as angiotensin-converting enzyme
(ACE) inhibitors and angiotensin receptor blockers (ARB),
as that seen in the general population? And what is the
optimal level of blood pressure for protecting against
cardiovascular disease and progressive allograft dysfunction? Is it 140/90 mm Hg? Is it 130/80 mm Hg? Or, should
the goal be modified based on comorbid diseases? Many, if
not most, transplant patients have either diabetes and/or an
estimated GFR below 60 mL/min/1.73 m2, and probably
would benefit from lower blood pressure goals. As will
be discussed later in this article, many of these questions
remain unanswered. It is the opinion of these authors that
until more is known, we should consider the data derived
from studies in the general population as being relevant
to treatment choices and goals in kidney transplant
*Corresponding author: Matthew R. Weir, MD, Division of
Nephrology, Department of Medicine, University of Maryland
School of Medicine, Baltimore, MD. Tel: (410) 328-5720;
fax: (410) 328-5685.
E-mail: [email protected]
Pathophysiology of Hypertension
The pathogenesis of posttransplant hypertension is
poorly characterized. Multiple factors are likely involved
1933-1711/$ - see front matter Ó 2011 American Society of Hypertension. All rights reserved.
M.R. Weir and D.J. Salzberg / Journal of the American Society of Hypertension 5(5) (2011) 425–432
Retention of sodium, and consequent volume expansion,
explain a distinctive characteristic of posttransplant hypertension, specifically, the loss of nocturnal reduction of blood
pressure.23 In the general population, loss of nocturnal reduction of blood pressure is associated with left ventricular
hypertrophy, lacunar stroke, and microalbuminuria.24 Interestingly, some studies have associated chronic cyclosporine
therapy with lack of nocturnal blood pressure reduction
when measured with ambulatory blood pressure monitoring
Transplant Renal Artery Stenosis
Figure 1. Calcineurin inhibitors and hemodynamic effects.
in the genesis of hypertension,7–11 the most important of
which may reside in the native diseased kidneys. In addition, the chronic use of calcineurin inhibitors (i.e., tacrolimus and cyclosporine), with or without corticosteroids,
induces preglomerular vasoconstriction, which activates
sodium conserving mechanisms within the kidney. The intrarenal vasoconstriction is likely mediated by angiotensin
II, endothelin, and possibly other mediators. Of these,
angiotensin II and endothelin are likely the most important
(Figure 1).12–21 Additionally, there may be other factors,
such as the development of arteriolopathy, or interstitial
fibrosis and tubular atrophy, which may be related to the
chronic administration of calcineurin inhibitors, which
result in an increase in blood pressure.22 However, it is clear
that with both cyclosporine and tacrolimus, that they
increase both systemic and renal vascular resistance. Other
important risk factors include: (1) preexisting recipient
factors such as pretransplant hypertension, (2) donorspecific factors such as hypertension in the donor, (3) subsequent development of transplant renal artery stenosis, (4)
development of chronic allograft dysfunction, and (5)
external behavioral factors such as recipient weight gain.
Progressive dysfunction in the transplanted kidney may
also contribute to blood pressure elevation via impairment
of sodium and water retention. Some of the processes that
may lead to worsening of graft function include calcineurin
inhibitor nephrotoxicity, thrombotic microangiopathy,
chronic antibody-mediated rejection, recurrent primary
kidney disease, or de novo glomerulonephritis.8,10,11
In large part, posttransplant hypertension is characterized
by sodium and water retention with associated volume
expansion along with increased sympathetic nervous system
activity, intrarenal18 (afferent glomerular arteriole) vasoconstriction, and lower levels of plasma renin. Lower levels of
plasma renin could also be indicative of higher intrarenal
levels of angiotensin II and endothelin with subsequent
sodium and water retention.
Transplant renal artery stenosis may occur in 10% or more
in renal transplant recipients (range, 1%–23%), and the incidence of reported cases is increasing with the prevalent use of
Doppler ultrasound and magnetic resonance imaging.12,25
Whether this increase is clinically relevant is unknown.
Usually transplant RAS is detected between 3 months to 2
years posttransplant, but cases have occurred even years later.
Kidneys with multiple renal arteries implanted on a common
aortic patch have a higher prevalence of late renal artery
stenosis 6 months to 3 years posttransplant.26 Other risk
factors associated with RAS include infection with cytomegalovirus and delayed graft function. Unless patients have
resistant hypertension, or develop renal dysfunction with
progressive blood pressure elevation (with or without RAS
blockers), a transplant renal artery duplex is not routinely
performed in most centers. Thus, the incidence of renal artery
stenosis is likely underreported.
A renal artery duplex can be a useful screening tool.27,28
A renal duplex can be accurate, but depends on the experience of the sonographer and the orientation of the kidney
and the body habitus of the patient. If one defines stenosis
as more than a 50% reduction in lumen diameter, a peak
systolic velocity of 2.5 m/sec was associated with a sensitivity and specificity of 100% and 95% in a study of 109
transplant patients when compared with digital subtraction
angiography.27 In general, most reports indicate the benefits
of screening with a renal duplex.28 Magnetic resonance
angiography or computed tomography angiography can
be used for definitive evaluation. As the true incidence of
transplant renal artery stenosis is unknown, the clinical
benefit of correction is not clear, and the subject of center
case series. In our experience, angioplasty and stenting is
often preferred, depending on the location of the stenotic
area. However, there are a limited number of small reports
on angioplasty and/or stenting on long-term outcome.29,30
The precise role of hypertension on patient and allograft
outcome posttransplantation has been difficult to define
because hypertension is both the cause of, and a consequence of, kidney disease. What is well described in the
M.R. Weir and D.J. Salzberg / Journal of the American Society of Hypertension 5(5) (2011) 425–432
appropriate. Whether to use thiazide or loop type diuretic
depends on the estimated GFR and whether the treating
physician feels the volume expansion process is a significant
contributing factor to the hypertension. Although not well
studied, it is our opinion that some type of diuretic therapy
is often required to facilitate achievement of adequate
blood pressure control. Because thiazide diuretics may
lose some of their volume reducing benefits with estimated
GFR below 50 mL/min/1.73 m2, more powerful diuretics,
such as chlorthalidone or metolazone, or loop diuretics,
may be a more appropriate. However, thiazide diuretics
may have blood pressure lowering effects outside of their
ability to reduce intravascular volume, such as acting as
direct vasodilatory agents, which may remain effective
with estimated GFR below 50 mL/min/1.73 m2. Unfortunately, there are no clinical studies that have examined
this important question. Of note, many patients can achieve
blood pressure control in the absence of diuretic support.
Calcium channel blockers are an effective class of medications to lower blood pressure in kidney transplant recipients. In the general population, they provide effective
reduction of blood pressure regardless of age, gender,
ethnicity, and salt intake, which may explain why they
are also effective in the kidney transplant patient.35 In addition, they also appear to reverse some of the intrarenal
vasoconstriction caused by calcineurin inhibitors.35–37
Some clinicians prefer to use calcium channel blockers
as, opposed to diuretics, to facilitate achievement of blood
pressure control in kidney transplant patients, in conjunction with other drugs. We specifically prefer to use the class
of dihydropyridine calcium channel blockers for two
reasons: First, as will be discussed later, many patients
will derive cardiovascular benefits from beta-blockers.
Beta-blockers are safer when used with dihydropyridine
as opposed to nondihydropyridine calcium channel
blockers to avoid additive effects of reducing atrioventricular node conduction. Second, nondihydropyridine calcium
channel blockers interact with cyclosporine, and to a lesser
extent tacrolimus, to raise the serum levels of these drugs.
Some physicians have purposefully used diltiazem and
verapamil to cut the dose of calcineurin inhibitors by
60%–70% as a cost saving strategy. However, one must
be extra vigilant in monitoring drug levels of calcineurin
inhibitors when using nondihydropyridine calcium channel
blockers. Of note, nicardipine, a dihydropyridine calcium
channel blocker, also interacts and raises cyclosporine
and tacrolimus levels.
Beta-blockers are another important class of antihypertensive agents which should be considered in the treatment
for hypertension in the kidney transplant patient. Transplant
patients, whether diabetic or not, are at much greater risk
for cardiovascular events as compared with the general
population.38 Thus, beta-blockade may have a role during
the perioperative period to protect against myocardial
ischemia, and for long-term management of hypertension.
Figure 2. Association of allograft survival and systolic blood
pressure at 1-year posttransplant (P < .0001). (Adapted from
Opelz G, Wujciak T, Ritz E. Association of chronic kidney
graft failure with recipient blood pressure. Collaborative Transplant Study. Kidney Int. 1998 Jan;53(1):217–22 PMID
literature is that posttransplant hypertension is associated
with an increased risk for acute rejection, in particular
with African Americans, shorter duration of graft survival,
and the development of left ventricular hypertrophy.31–33
The Collaborative Transplant Study was a multicenter
observational study involving 262 centers and 29,751
subjects whose data were collected between 1987 and
1995.32 Using a multivariate regression model, they demonstrated a striking association between increased systolic
blood pressure and decreased allograft survival, regardless
of diastolic blood pressure (Figure 2). There was a continuous inverse relationship between systolic blood pressure
above 120 mm Hg and duration of graft function. Systolic
blood pressures below 140 mm Hg were also associated
with better patient survival.
In a historical cohort study of adult allograft recipients,
Mange and colleagues34 noted that for each 10 mm Hg
increase in systolic, diastolic, and mean blood pressure,
there was a 15%, 27%, and 30% reduction, respectively, in
the renal allograft survival. Because higher levels of blood
pressure are associated with greater degrees of graft
dysfunction (in addition to decreased survival and higher
proteinuria), it suggests that lower levels of blood pressure
may be advantageous for both patient and graft survival.
However, there are no prospective studies to evaluate the
cardiovascular benefits of planned reduction of blood pressure to any goal in kidney transplant patients, let alone lower
goals such as 120 or 130 mm Hg.
Treatment of Hypertension
Give that posttransplant hypertension is often characterized by a lower renin, volume-expanded state, it would
make sense that some form of diuretic therapy would be
M.R. Weir and D.J. Salzberg / Journal of the American Society of Hypertension 5(5) (2011) 425–432
in cardiovascular events in kidney transplant recipients. The
only prospective, randomized controlled trial involving
transplant patients comparing RAS blockers versus placebo
was stopped prematurely because of a lack of primary events
(composite of all-cause mortality, cardiovascular morbidity,
and graft failure).48 However, this study did demonstrate
better blood pressure control in the RAS blocker (candesartan) arm, and urinary protein excretion decreased during the
study by 28.6% in the candesartan arm and increased by
15.4% in the control arm. Serum creatinine and potassium
increased in the candesartan-treated patients, but these
changes were small and rarely of clinical consequence.48
Despite the lack of prospective clinical trials, there are
a number of retrospective studies that illustrate the potential
benefit of RAS blocking drugs on clinical outcomes in
kidney transplant recipients. In a recent retrospective
review of more than 2000 recipients of kidney transplants
at the University of Vienna, investigators noted that the
10-year survival rates were 74% in patients receiving either
an ACE inhibitor or an ARB as part of their antihypertensive regimen, and only 53% in patients not receiving these
agents.49 Their results were even more remarkable when
one considers that the group receiving the RAS blockers
were older and required a larger number of antihypertensive
medications, as compared with the group not receiving
these agents. They were also more likely to have type 2 diabetes and evident cardiovascular disease. Although selection bias limits the interpretation of the results, the data
are intriguing, and suggest that there may be an important
opportunity to employ RAS blocking drugs as part of an
antihypertensive regimen in an effort to reduce cardiovascular events in transplant patients.
Premasathian and colleagues constructed a proportional
hazards model to assess the interactive effects of the degree
of blood pressure control and type of antihypertensive medications on graft loss in more the 1600 kidney transplant recipients.38 Although their study was retrospective, their Cox
regression model illustrated the advantage of calcium
channel blockers for reduced risk of graft loss. When they
stratified the subjects into blood pressure levels and
compared the rates of graft survival between those patients
receiving calcium channel blockers and those receiving
RAS blocking drugs, there was a favorable effect on graft
survival specific to those subjects receiving either an ACE
inhibitors or ARB in the cohort of subjects with the highest
systolic blood pressure. However, to establish true causality
between these drugs and the previous outcomes, one must
necessarily integrate results of retrospective studies with
results from future randomized clinical trials.
Heinze and colleagues49 studied 436 kidney transplant
recipients who had delayed graft function. Approximately
half of those patients (n ¼ 181) were given either an
ACE inhibitor or ARB at the time of transplantation. Those
patients who received the RAS blocker had an improvement in 10-year graft survival compared with those who
The heart rate–lowering effects and ability to reduce
myocardial oxygen demand may be the key beneficial
effects for the transplant patient. Theoretically, they target
the increase in the sympathetic nervous activity, which is
often seen in transplant recipients. Beta-blockers have
been used effectively in transplant patients to control blood
pressure.39 However, traditional vasoconstricting betablockers (e.g., metoprolol, atenolol) may cause fatigue
and may be associated with metabolic consequences such
as hyperkalemia, weight gain, and worsening of insulin
resistance and increased serum triglycerides. The vasodilating beta-blockers with selective alpha 1 blocking effects,
such as carvedilol, labetalol, or nebivolol may be better
tolerated, and perhaps may have fewer associated metabolic
issues compared with traditional beta-blockers. However,
there are no data on the differential effects of betablockers on symptoms and metabolism in the transplant
patient receiving corticosteroids and calcineurin inhibitors.
Alpha-blockers also represent an important class of antihypertensive agents for transplant patients. Prostatic hypertrophy and bladder detrusor dysfunction secondary to
diabetic autonomic neuropathy are not uncommon problems
in transplant recipients. Thus, in the hypertensive patient
with voiding difficulty, alpha-blockers may be useful.
However, these agents can cause orthostatic symptoms and
have no proven benefit in reducing mortality in the general
Drugs that block the RAS, such as ACE inhibitors and
ARBs, are attractive considerations, considering their known
benefits in the general population for reducing cardiovascular
events and kidney disease progression. However, there are
some concerns associated with use of these drugs in transplant patients. First, monotherapy with an ACE inhibitor or
ARB is rarely successful in controlling blood pressure in
the transplant patient, likely because of volume expansion.
They also can induce anemia (a 5%–15% reduction from
erythropoietin resistance), hyperkalemia, and a functional
decrease in GFR.40,41 The latter may raise concerns for acute
rejection. Additionally, in the setting of transplant renal
artery stenosis, these agents may precipitate acute kidney
There are multiple theoretical reasons for the use of RAS
blockers in the treatment of hypertensive kidney transplant
recipients. These include reductions in systemic blood pressure, intraglomerular capillary pressure, and proteinuria.39,43
In addition, calcineurin inhibitor nephrotoxicity, may, in part
be related to excess effect of angiotensin II (Figure 1).44,45
RAS blockers may block angiotensin type 1 receptor antibodies, which may be associated with vascular rejection.46
Finally, RAS blockers, as part of an effective blood pressure–lowering regimen, may reduce primary and secondary
cardiovascular events, as seen in the general population.47
Unfortunately, there are no completed prospective studies
demonstrating the advantage of RAS blockers in protection
against graft loss, progression of kidney disease, or reduction
M.R. Weir and D.J. Salzberg / Journal of the American Society of Hypertension 5(5) (2011) 425–432
Figure 3. Decrease in proteinuria with use of either angiotensin-converting enzyme inhibitor or angiotensin receptor blockers with at
least 12 months of follow-up. (Adapted from: Hiremath S, Fergusson D, Doucette S, Mulay AV, Knoll GA. Renin angiotensin system
blockade in kidney transplantation: a systematic review of the evidence. Am J Transplant. 2007 Oct;7(10):2350–60). ACEI, angiotensin
converting enzyme inhibitor; ARB, angiotensin receptor blocker; CI, confidence interval.
studies are needed to define optimal levels of blood pressure and types of therapies to facilitate better long-term
patient and graft survival in kidney transplant recipients.
Taken together, clinical trials of antihypertensive therapeutics in kidney transplant recipients illustrates that, with diligence, hypertension can be adequately controlled.
did not (44% vs. 32%, respectively). Hiremath and
colleagues40 performed a systematic review of 21 randomized trials of 1549 patients to determine the effect of ACE
inhibition or ARB therapy on graft function and patient
survival after kidney transplantation. In this analysis, they
observed that drugs that block the RAS were associated
with a significant decrease in GFR (-5.8 mL/min), proteinuria (-470 mg/day) (Figure 3), and hematocrit (-3.5%).44,50
However, there was insufficient power to determine
whether there was an effect on patient or graft survival.
The authors suggest that there is a tradeoff between the
beneficial effects of proteinuria reduction and potential
cardiac protection, with the development of anemia and
lowered GFR.
In addition to specific antihypertensive therapy, modification of the immunosuppression regimen may also help
to achieve adequate blood pressure control. Corticosteroid
minimization, or avoidance, is helpful, because these drugs,
particularly in higher doses, have mineralocorticoid effects.
Calcineurin inhibitor minimization or withdrawal51 may
also be important to help reduce blood pressure. Within
the class of calcineurin inhibitors, when using has less
hypertensive effect than cyclosporine22 so conversion
from one calcineurin inhibitor to the other, may be a consideration in some patients.
Our algorithm for treatment of posttransplant hypertension is to use either a diuretic (either thiazide or loop
diuretics) or a calcium channel blocker, or both, supplemented this with a RAS blocker. If there is evidence of
azotemia with this approach, we reduce the diuretic dose
or switch to a calcium channel blocker. We also recommend using beta-blockers in patients at risk for, or who
have evidence of cardiovascular disease. We also recommend the use of alpha-blockers in patients with voiding
difficulty. Fixed-dose combinations may improve medication adherence in subjects who have complex multidrug
regimens. As in the general population, tolerability is an
important consideration with all choices and doses of
antihypertensive agents. Drug–drug interactions and adjustment of dosing also need to be carefully considered. More
Measuring Blood Pressure
As in the general population, blood pressure in the transplant recipient is dynamic. Often, blood pressure dipping at
night is less evident. It is likely that ‘‘white coat’’ and
‘‘masked’’ hypertension are as common in the transplant
population as they are in the general population. Ambulatory blood pressure monitoring and home blood pressure
monitoring may help in deciding about the adequacy of
treatment. Unfortunately, there is little published information on the utility of these measures in guiding treatment.
Bulleted Practical Recommendations
1. Kidney transplant patients are at increased risk for
cardiovascular disease because of the constellation of
reduced GFR, diabetes mellitus, and cardiovascular
risk factors (both traditional and nontraditional).
2. Patient survival is likely improved with a blood pressure goal below 130/80 mm Hg, given the information
from data registries. A blood pressure goal below 130/
80 mm Hg (or perhaps below 120/70 mm Hg) may be
optimal for prolonging graft function.
3. Choice of antihypertensive medications posttransplantation depends on the subject’s comorbid conditions
and clinical examination. Often patients will require
some type of diuretic support based on their volume
status and level of kidney function. Dihydropyridine
calcium channel blockers may substitute for diuretics
in some patients and may be particularly helpful in
attenuating some of the intrarenal vasoconstriction
associated with calcineurin inhibitor use.
M.R. Weir and D.J. Salzberg / Journal of the American Society of Hypertension 5(5) (2011) 425–432
5. Sorof JM, Sullivan EK, Tejani AMIR, Portman RJ.
Antihypertensive medication and renal allograft
failure: a North American Pediatric Renal Transplant
Cooperative Study report. J Am Soc Nephrol 1999;
6. Chobanian AV, Bakris GL, Black HR, Cushman WC,
Green LA, Izzo JL Jr, et al. The Seventh Report of the
Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure: the
JNC 7 Report. JAMA 2003;289:2560–72.
7. Luke RG. Pathophysiology and treatment of posttransplant hypertension. J Am Soc Nephrol 1991;2:
8. Ponticelli C, Montagnino G, Aroldi A, Angelini C,
Braga M, Tarantino A. Hypertension after renal transplantation. Am J Kidney Dis 1993;21:73–8.
9. Raine AE. Does antihypertensive therapy modify
chronic allograft failure? Kidney Int 1995;(Suppl 52):
10. Sanders CE Jr, Curtis JJ. Role of hypertension in
chronic renal allograft dysfunction. Kidney Int 1995;
(Suppl 52):S43–7.
11. Vianello A, Mastrosimone S, Calconi G, Gatti PL,
Calzavara P, Maresca MC. The role of hypertension
as a damaging factor for kidney grafts under cyclosporine therapy. Am J Kidney Dis 1993;21:79–83.
12. Bruno S, Remuzzi G, Ruggenenti P. Transplant renal
artery stenosis. J Am Soc Nephrol 2004;15:134–41.
13. Conte G, Dal CA, Sabbatini M, Napodano P, De NL,
Gigliotti G, et al. Acute cyclosporine renal dysfunction
reversed by dopamine infusion in healthy subjects.
Kidney Int 1989;36:1086–92.
14. Curtis JJ, Luke RG, Jones P, Diethelm AG. Hypertension in cyclosporine-treated renal transplant recipients
is sodium dependent. Am J Med 1988;85:134–8.
15. Gardiner DS, Watson MA, Junor BJ, Briggs JD,
More IA, Lindop GB. The effect of conversion from
cyclosporin to azathioprine on renin-containing cells
in renal allograft biopsies. Nephrol Dial Transplant
16. Kon V, Sugiura M, Inagami T, Harvie BR, Ichikawa I,
Hoover RL. Role of endothelin in cyclosporine-induced
glomerular dysfunction. Kidney Int 1990;37:1487–91.
17. Kopp JB, Klotman PE. Cellular and molecular mechanisms of cyclosporin nephrotoxicity. J Am Soc Nephrol
18. McNally PG, Feehally J. Pathophysiology of cyclosporin
A nephrotoxicity: experimental and clinical observations. Nephrol Dial Transplant 1992;7:791–804.
19. Moran M, Mozes MF, Maddux MS, Veremis S,
Bartkus C, Ketel B, et al. Prevention of acute graft rejection by the prostaglandin E1 analogue misoprostol in
renal-transplant recipients treated with cyclosporine
and prednisone. N Engl J Med 1990;322:1183–8.
4. The data concerning the use of beta-blockers in posttransplant recipients is limited. Because of the
increased risk for cardiovascular disease or evident
cardiovascular disease in this population, betablockers may be helpful. Prospective studies are needed
to examine their potential benefits in the perioperative
and immediate postoperative periods.
5. Drugs that block the RAS should be considered for use
in most kidney transplant subjects after stable graft
function is obtained. Their use may offer both kidney
and cardiovascular disease protection. In transplant
patients, these agents are effective in reducing proteinuria. It is possible that, as in the general population with
native kidney disease, that time-varying albuminuria
may be predictive of both kidney and cardiovascular
events. Consequently, therapeutic strategies that reduce
proteinuria may be an important biomeasure of appropriate treatment. However, there are no prospective
clinical studies to support these hypotheses.
6. The treatment of hypertension in kidney transplant
subjects is complicated by polypharmacy with subsequent increased risk for drug–drug interactions. Transplant patients need to be educated on the importance
of blood pressure control and lifestyle modification,
and that often multiple antihypertensive drugs will be
7. Minimization or avoidance of corticosteroids or calcineurin inhibitors may be helpful in controlling blood
pressure in kidney transplant recipients.
8. Transplant renal artery stenosis, as a cause of graft
dysfunction and resistant hypertension, needs to be
considered in all patients. Renal artery duplex can be
a useful screening tool.
We thank Tia A. Paul, University of Maryland School of
Medicine, Baltimore, MD, for expert secretarial assistance.
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