Antihypertensive Drug Side Effects in the

Hypertension Detection and

Follow-up Program
J. DAVID C U R B , KENNETH SCHNEIDER, JAMES O. TAYLOR, MORTON MAXWELL,
AND NEIL SHULMAN

SUMMARY The 5485 participants in the Hypertension Detection and Follow-up Program, Stepped-
Care group form one of the largest groups to date on which detailed surveillance of long-term
antihypertensive therapy and drug side effects has been reported. During a 5-year period, among all
hypertensive persons (mild, moderate, and severe combined) who were not taking antihypertensive
medications at the beginning of the study and who attended the clinic at least once during the 5-year
trial, a total of 9.3% had definite or probable side effects severe enough to cause discontinuation of the
drug treatment in question. Less than 1% of active participants required hospitalization for side
effects. No death that could be attributed to side effects was detected. Thus, the Hypertension
Detection and Follow-up Program data, which have previously demonstrated the beneficial effects of
antihypertensive therapy, confirm the relative safety of such therapy.
(Hypertension 11 [Suppl H]: II-51-II-55, 1988)

KEY WORDS • blood pressure • treatment • adverse reactions • prospective

surveillance • cholesterol • reserpine

T HE beneficial effects of drug treatment have

been demonstrated in individuals with hyper-
surveillance data on antihypertensive drugs are avail-
able. The data presented here represent a description of
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tension. '~3 The adverse effects of antihyper-
tensive medications also have been well document-
ed.6' 7 While high blood pressure can be safely treated
in most individuals, side effects of drugs are relatively
frequent and may have notable effects on quality of life
and compliance with the prescribed regimens.
Each possible side effect encountered by a therapist
or practitioner is a combination of the patient's percep-
tion, the clinician's preconceptions, and the actions of
the drug. While the Hypertension Detection and Fol-
low-up Program (HDFP) was not designed to study the
side effects of drugs in comparison with placebo, its
Stepped-Care category does constitute one of the larg-
est cohorts (n = 5485) from which detailed clinical
From the National Institute on Aging, Bcthesda, Maryland (J.D.
Curb); Duke University Medical Center, Durham, North Carolina
(K. Schneider); Harvard University Medical School, Boston, Mas-
sachusetts (J.O. Taylor); University of California Los Angeles, Los
Angeles, California (M. Maxwell); and Emory University Medical
School, Atlanta, Georgia (N. Shulman).
Supported by National Heart, Lung, and Blood Institute Con-
tracts NO1-HV-124 (33-42), NO1-HV-229 (31, 37-39, 45), NO1-
HV-32933, NO1-HV-72915, and NO1-HV-82915.
Address for reprints: Dr. Curb, National Institute on Aging,
Epidemiology, Demography, and Biometry Program, Federal
Building, Room 612, 7550 Wisconsin Avenue, Bethesda, MD
20892.
0-51
the experience of the HDFP with antihypertensive drug
side effects.
Methods
Data relevant to adverse drug reactions were gath-
ered through a number of methods in the HDFP. These
included questions asked in the home annually by
nontherapist interviewers, responses elicited by ques-
tionnaire in the clinic, information provided by the
therapist in the clinic, and information from the labora-
tory and electrocardiogram (ECG).
In the clinic's questionnaires, each stepped-care
participant was asked at baseline and at each subse-
quent clinical visit during the first year of the HDFP a
set of 12 standard questions relating to nonspecific
symptoms often associated with adverse drug side ef-
fects.8 These questions and the answers to them were
used as an index of the patient's perceptions of symp-
toms related to side effects.
Data on clinically detected drug side effects present-
ed in this article are based on summary information on
stepped-care participants provided by the HDFP staff
therapist or physician on the basis of all available
clinical information. Treatment was initiated with a
stepped-care protocol using drugs that were approved
by the Food and Drug Administration for use at the
 11-52 ANTIHYPERTENSIVE DRUG EFFECTS SUPPL U HYPERTENSION, VOL 11, No 3, MARCH 1988
beginning of the trial in 1973, including chlorthalidone
in step 1, reserpine or methyldopa in step 2, hydrala-
zine in step 3, guanethidine in step 4, and additional or
alternative drugs in step 5. Although this was the stan-
dard protocol, maintenance of blood pressure control
was the primary goal of HDFP therapy, and when
problems such as suspected side effects occurred, the
HDFP therapist modified individual regimens as clini-
cally necessary.
During the entire program, discontinuation of treat-
ment with any antihypertensive medication required
the completion of special study forms to provide expla-
nation for discontinuation of treatment with that drug;
other data were available on routine clinical visit
forms.9 The final classification of each side effect
event was based on the central physician's review of
all prior and subsequent clinical data relative to the
event, including specific side effect follow-up records.
To reduce bias due to past experience with antihyper-
tensive medications and their side effects, all individ-
uals already receiving antihypertensive therapy at en-
try into the study were excluded from this analysis.
The effect of thiazides on mean serum cholesterol
values was examined for all 5 years of the study. The
quantification of cholesterol was accomplished using a
Technicon SMA 12/60 (TM) multichannel analyzer
using the Leibermann-Burchard method in a CDC
standardized laboratory. Overall analytical drift was
monitored by one-blind and two-unblinded tech-
niques. These three methods revealed a small, random
analytical drift that was judged by all committees to be
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nonsignificant.
Results
During the year in which the patient symptom ques-
tionnaire was administered, 15,076 visits were made
to HDFP clinics by stepped-care participants not on
antihypertensive medication at baseline. At baseline,
before therapy was initiated, 74.8% of these individ-
uals reported at least one of the 12 symptoms. During
thefirstyear of therapy, 75.4% reported having at least
one of the symptoms during at least one clinical visit.
New symptoms (not reported at baseline) were much
less frequent in all race and sex groups (14.3% over-
all): black and white differences were small, but male
and female differences were significant (/?<0.05).
Forty-five percent of individuals reporting symptoms
during therapy had reported the same symptom before
therapy was initiated.
TABLE 1. Number and Percentage of Active Participants* with Side Effects Resulting in Drug Discontinuation by
Estimated Probability That the Event Was a True Side Effect
Definite or probable
Baseline BP Total active
(mm Hg) participants n %
90-104 2756 236 8.6
105-114 730 80 11.0
>115 358 43 12.0
Total 3844 359 9.3
•Participants regularly followed in an HDFP clinic.
Modified from Curb et al.8 with permission.
During the 5-year follow-up, stepped-care partici-
pants made 172,569 clinical visits to the 14 HDFP
clinical centers. At the end of thefifthyear, 79% of the
participants were active in the program. During this
period, blood pressures (BP) among the stepped-care
participants were reduced, on the average, by 28.7 mm
Hg systolic and 17.0 mm Hg diastolic. Of those seen at
the fifth annual clinical visit, 74.2% were at or below
their blood pressure goal. Among 3844 individuals
who were not receiving medications at the beginning
of the trial and whoremainedactive participants in it, a
total of 1258 participants (32.7%) experienced at least
one possible adverse reaction to a medication, which
prompted the clinical therapist to discontinue the use of
one or more drugs (Table 1); 40% of these individuals
had more than one such event. Rates of side effects by
baseline blood pressure strata and indications of
whether the event was thought to be possibly, prob-
ably, or definitely a side effect are shown. Only 9.3%
of stepped-care participants were reported to have
probable or definite side effects during the 5 years.
Such side effects were reported in 8.6% of those with
mild hypertension (diastolic BP, 90-104 mm Hg), in
11.0% of those with moderate hypertension (diastolic
BP, 105-114 mm Hg), and in 12.0% of those with
severe hypertension (diastolic BP, >115 mm Hg).
Figure 1 summarizes the percentage of active
stepped-care participants experiencing side effects
(possible + probable + definite) among active
stepped-care participants for each of the 5 years of
follow-up by race and sex. During this period, 22.9%
of the black women, 26.6% of the black men, 33.7%
of the white women, and 40.9% of the white men had
drug treatment discontinued because of suspected side
effects. There was a decreasing percentage of partici-
pants having treatment discontinued because of side
effects in all these groups over time, with the rates
during the fifth year being less than half those during
the first year.
There were few life-threatening side effects, and
there were no deaths that could be directly attributed to
drug side effects. Only 23 individuals (<1%) were
hospitalized for suspected side effects. The frequency
of reported side effects was highest in those in the 50-
to 59-year-old age group for all HDFP drugs except
hydralazine, for which the incidence was greatest in
the 40- to 49-year-old group. The incidence of side
effects was lowest in the 60- to 69-year-old group for
all drugs. Similar patterns were seen when the criteria
Side effects
Possible Total
n % n %
642 23.3 878 31.9
157 21.5 237 32.5
100 27.9 143 39.9
899 23.4 1258 32.7
 HDFP ADVERSE EFFECTS/Curfc et al. 11-53

fects. This was true for almost every side effect cate-
gory in which the number of events was large enough
o to make reasonable comparisons. For individuals tak-
ID ing specific drugs, side effects reported by the HDFP
W participants were, in general, not severe and were con-
•a sistent with side effects of that medication previously
reported in the literature.
White Uale
Among the known side effects of antihypertensive
White Female
Black U.la
drugs, sexual problems in males are often of major
Black Female concern. Impotence was the most frequently reported
problem for all drugs, while decreased libido was the
next most common complaint for all drugs except
Year guanethidine, which apparently caused more retro-
FIGURE 1. Percentage ofactive participants who experienced grade ejaculation than other drugs. Guanethidine was
side effects causing discontinuation of drug treatment in each the drug most commonly associated withreportedsex-
year of therapy. ual problems; more than 10% of the male participants
who took it had the drug therapy discontinued for pos-
were restricted to definite plus probable side effects. sible sexually related side effects. Use of chlorthali-
As shown in Table 2, the reported frequency of specif- done, methyldopa, and reserpine was also discontin-
ic individual side effects was also lower in the oldest ued relatively frequently because of sexually related
age group (60-69 years at baseline) for most side ef- problems, while spironolactone was less frequently

TABLE 2. Incidence of Selected Adverse Drug Reactions Among Active Participants by Age
Age
(years)
30-39 40-49 50-59 60-69 Total
Adverse reaction n Rate/100 n Rate/100 n Rate/100 n Rate/100 n Rate/100
Angina 3 0.5 9 0.0 10 0.8 2 0.3 24 1.8
Arrhythmias 3 0.5 12 1.0 15 1.2 3 0.4 33 0.9
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Hypotension/outhostasis 15 2.3 23 2.0 20 1.6 12 1.5 70 0.6

Mimon GI 38 5.7 78 6.7 93 7.5 41 5.2 249 6.5
Pcpic ulcer/GI bleeding 0 0.0 6 0.5 9 0.7 5 0.6 20 0.5
Liver abnormalities 7 1.1 6 0.5 8 0.6 4 0.5 25 0.7
Arthritis/arthralgias 8 1.2 10 0.9 8 0.6 4 0.5 30 0.8
Muscle cramping 5 0.8 6 1.4 19 1.5 9 1.1 49 1.3
Lupus/flu syndrome 3 0.5 5 0.4 6 0.5 2 0.3 16 0.4
Dermatitis 17 2.6 37 3.2 46 3.7 26 3.3 126 3.3
Asthma 1 0.2 4 0.3 0 0.0 0 0.0 5 0.1
Nasal stuffiness 22 3.4 40 3.4 30 2.4 10 1.3 102 2.7
Sexual 43 6.6 61 5.2 70 5.6 15 1.9 189 4.9
Depression 28 4.3 58 5.0 40 3.2 11 1.4 137 3.6
Nightmares 19 2.9 36 3.1 28 2.3 8 1.0 91 2.4
Other psychiatric 3 0.5 5 0.4 1 0.1 1 0.1
Dizziness/syncope 28 2.0 51 4.4 57 4.6 29 3.7 165 4.3
Headache 20 3.1 22 0.6 15 1.2 9 1.1 66 1.7
Lethargy 32 4.9 59 5.1 56 4.6 18 3.1 240 6.2
Drowsiness 46 7.1 96 8.3 74 6.9 24 3.1 240 6.2
Weakness 19 2.9 41 3.5 47 3.8 25 3.2 132 3.4
Hypokalemia 13 2.0 21 1.8 17 1.4 8 1.0 59 1.5
Gout/hyperuricemia 5 0.8 16 1.4 22 1.8 6 0.8 49 1.3
Diabetes/hyperglycemia 5 0.8 18 1.6 27 2.1 13 1.7 63 1.6
Gynecomastia 10 1.5 16 1.4 31 2.5 8 1.0 65 1.7
Hypercalcemia 2 0.3 2 0.2 3 0.2 4 0.5 11 0.3
Total 207 31.9 406 34.8 436 35.1 209 26.6 258 32.7
Modified from Curb et al.* with permission.
 11-54 ANTfflYPERTENSIVE DRUG EFFECTS SUPPL H HYPERTENSION, VOL 11, No 3, MARCH 1988
thought to cause such problems. Only six females dis-
continued medications because of sexually related
drug side effects.
Figure 2 shows the data on the annual changes in
serum cholesterol during 5 years for thiazide-treated
stepped-care participants. In order to use all cholester-
ol data available on each patient, the cholesterol values
for every annual visit and cholesterol checks per-
formed 6 months before or after each annual visit were
averaged to give the yearly mean serum cholesterol
concentration. Because patients were seen every 4
months, the yearly value for each patient was usually
an average of two or three determinations. Among
those taking chlorthalidone or thiazides alone or in
combination with reserpine or methyldopa for the en-
tire 5-year period, cholesterol at thefirstyear increased
by 4 mg/dl, followed by a continuous decline amount-
ing to 9 mg/dl at the fourth year, and is stable at the
fifth year. Similar trends were noted in all race, sex,
and age groups. Among those treated with a similar
regimen, an increase in serum cholesterol during the
initial 6-month period was also noted.
Analyses designed to examine the possibility that
the findings were due to a cohort effect suggest that
even though the number of participants decreased from
year to year, a selection process, if it were operative,
did not result in different cholesterol values for those
patients on longer-term therapy.
Discussion
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Because of the absence of a blinded-placebo group
in the HDFP, the findings reported here must be con-
sidered as the results of a study of clinical surveillance
for drug side effects and not as a controlled clinical
trial for comparing those taking drugs and those not
taking them. The data presented do indicate, however,
that the number of individuals who report side effect-
like complaints at the beginning of a program, while
not on antihypertensive medication, is substantial
(74.8%).
The frequency of possible drug side effects severe
enough to cause discontinuation of drug therapy in the
1 2 3 4 5 With respect to the mortality experience for HDFP
Years of Follow—up
FIGURE 2. Mean serum cholesterol by year among HDFP
Stepped-Care participants continuously on chlorthalidone.
HDFP is consistent with clinical experience in the
treatment of hypertension. There are, however, few
well-documented reports of the long-term occurrence
of side effects of antihypertensive therapy. In the
HDFP, although relatively standard drug regimens
were encouraged, blood pressure lowering and, thus,
compliance to the drug regimen took precedence over
the particular medications used. Therapists and physi-
cians were sensitive to actual, potential, and patient-
perceived side effects of the drugs that might affect
compliance, and they would discontinue use of a medi-
cation when a side effect was possible, if it were be-
lieved such an action would help to keep the patient
under active treatment. The HDFP analysis has also
shown that specific questions about patient perceptions
of nonspecific side effect-like symptoms will result in
at least one positive response in most patients at some
time during therapy. The situation is similar to that
faced by the clinician who often has similar goals in his
practice, and the data presented here should approxi-
mate what would be seen by such a practitioner.
Of some interest is the fact that side effects were not
reported more frequently in the older patients than in
the younger individuals. This observation tends to
agree with earlier reports from the European Working
Party on High Blood Pressure Study in the Elderly10
regarding therelativesafety of treating hypertension in
older patients.
hi several short-term studies, thiazide diuretics have
been associated with an increase in serum cholesterol
and triglyceride levels in normal and hypertensive pa-
tients.11"14 Most of these investigations involved acute
treatment with a duration of 1 year or less.
Two investigations for a longer period than 1 year,
the Framingham Study" and the Oslo clinical trial,16
reported there was no change in cholesterol levels in
hypertensive patients receiving diuretics for 2 years or
more. Others, including the Multiple Risk Factor In-
tervention Trial (MRFIT) group, have indicated a pos-
sible long-term increase in serum cholesterol.17"19
Thus, there are inconsistent results regarding the
effects of diuretics on serum cholesterol when admin-
istered for a short period of time versus over several
years. The HDFPresultsindicate a short-term increase
(1 year) followed by a long-term absolute decrease
in serum cholesterol among chlorthalidone-treated
participants.
Immediately after publication of the MRFTT re-
sults,20 which postulated a possible adverse effect for
the "special intervention" group with hypertension and
resting ECG abnormalities at baseline, the HDFP Co-
operative Research Group undertook extensive data
analyses on this subject. The basic aim of these further
analyses of the HDFP data was to determine whether in
a cohort selected to resemble MRFTT participants the
HDFP results would replicate those reported by
MRFIT.
participants with resting ECG abnormalities at base-
line, the trend of the mortality from all causes (i.e., the
HDFP primary end point) was in favor of stepped-care
 HDFP ADVERSE EFFECTS/Ciirfc et al.
treatment of mild hypertension. In other words, for
both cardiovascular and total mortality, the stepped-
care group with and without ECG abnormalities at
baseline experienced a more favorable outcome than
the referred-care group. In these respects, therefore,
the HDFP and MRFIT findings are not concordant. For
a much smaller and more restrictive MRFTT-like sub-
group of white males with small numbers of events,
coronary heart disease rates are higher in the stepped-
care group with ECG abnormalities. This is not true for
similarly selected groups of blacks or women.
The subgroup of the HDFP cohort that is most com-
parable to the MRFTT cohort is small, as is the number
of events, hence, variability in the estimates of treat-
ment differences could be substantial. It should be kept
in mind that the HDFP and the MRFTT programs had
fundamental design differences that make direct com-
parisons more difficult. The HDFP was a community-
based sample, whereas the MRFTT participants were
volunteers derived from many sources and were suc-
cessfully qualified in accordance with a relatively
complex algorithm. MRFTT cause of death is based on
committee review of all records and interview data,
whereas HDFP cause of death is based on a single
nosologist's coding of the death certificates. Substan-
tial differences in the type of events, such as coronary
heart disease, included rhight be anticipated.21 There-
fore, it is significant to note that the HDFP data do not
indicate a consistent problem with stepped-care ther*
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apy for persons with mild hypertension and with rest-
ing ECG abnormalities as was suggested by MRFTT
data. Detailed data and a more extensive discussion of
this issue are presented elsewhere. 22
In general, no new or unexpected trends in side
effects of the drugs used in the HDFP were noted in
this study. Follow-up for long-term drug toxicity has
been limited, but an analysis of the HDFP 5-year data
regarding the possibility of a relationship between re-
serpine use and breast tumor growth failed to show
evidence of such an association.23 Although there was
a high incidence of perceived side effects, the majority
of those events reported were relatively mild, and few
contributed to significant morbidity. Thus, the HDFP
data, which have previously demonstrated the benefi-
cial effects of vigorous antihypertensive treatment,
also affirm the relative safety of antihypertensive
therapy.
References
1. Veterans Administration Cooperative Study Group on Antihy-
pertensive Agents. Effect of treatment on morbidity in hyper-
tension. II. Results in patients with diastolic blood pressure
averaging 90 through 114 mm Hg. JAMA 1970;213:1143-
1152
2. Hypertension Detection and Follow-up Program Cooperative
Group. Five year findings of the Hypertension Detection and
Follow-up Program. I. Reduction in mortality of persons with
high blood pressure, including mild hypertension. JAMA
1979^242:2562-2571
H-55
3. Management Committee of the Australian National Blood
Pressure Study. The Australian Therapeutic Trial in Mild Hy-
pertension. Lancet 1980;l:1261-1267
4. Amery A, Birkerhager W, Brixko P, et al. Mortality and moT-
bidity results from the European Working Party on High Blood
Pressure in the Elderly Trial. Lancet 1985;l:135OT1354
5. Medical Research Council Working Party. Medical Research
Council Trial of Treatment of Mild Hypertension: principal
results. Br Med J 1985;291:97-104
6. Nies AS. Adverse reactions and interactions limiting the use of
antihypertensive drugs. Am J Med 1975^8:495-503
7. Moses C. Drug treatment of mild hypertension: adverse conse-
quences. Ann NY Acad Sci 1978;3O4:84-98
8. Curb JD, Borhani NO, Blaszkowski TP, Zimbaldi N, Fotiu S,
Williams W. Patient perceived side effects to antihypertensive
medications. Am J Prev Med 1985;l:36-4O
9. Curb JD, Borhani NO, Blaszkowski TP, Zimbaldi N, Fotiu S,
Williams W. Side effects of antihypertensive drugs in the Hy-
pertension Detection and Follow-up Program. JAMA 1985;
253:3263-3268
10. European Working Party on High Blood Pressure in the Elder-
ly. Third Interim Report of the European Working Party on
High Blood Pressure in the Elderly (EWPHE): antihyperten-
sive therapy in patients above age 60. Acta Cardiol (Brux)
1981;33:113-134
11. vanBrummelen P, Leuven JAG, vanGent CM. Influence of
hydrochlorothiazide on the plasma levels of triglycerides, total
cholesterol and HDL-cholesterol in patients with essential hy-
pertension. Curr Med Res Opin 1979;6:24-29
12. Gluck Z, Weidmann P, Mordasini R, et al. Increased serum
low-density lipoprotein cholesterol in men treated short-term
with the diuretic chlorthalidone. Metabolism 198029:240-245
13. Grimm RM, Leon AS, Hunninghake DB, Lenz K, Hannon P,
Blackburn H. Effect of thiazide diuretics on plasma lipids and
lipoproteins in mildly hypertensive patients. Ann Intern Med
1981;94:7-11
14. Goldman Al, Steele BW, Schnaper HW, Fritz AE, Frohlich
ED, Perry HM. Serum lipoprotein levels during chlorthalidone
therapy: Veterans Administration and the National Heart,
Lung, and Blood Institute Cooperative Study on Antihyperten-
sive Therapy: Mild Hypertension. JAMA 1980;244:1691-
1695
15. Kahnel WB, Gordon T, McGee D. Diuretics and serum-cho-
lesterol: the Framingham Study. Lancet 1977^:1362-1363
16. Helgoland A. Treatment of mild hypertension: afiveyear con-
trolled drug trial: the Oslo Study. Am J Med 1980;69:25-32
17. LasserNL, GranditsG, CaggiulaA.etal. Effects of antihyper-
tensive therapy on plasma lipids and lipoproteins in the Multi-
ple Risk Factor Intervention Trial. Am J Med 1984;2A:56-65
18. Stamler R, Stamler J, Grimm R, et al. Nutritional therapy for
high blood pressure. JAMA 1987^57:1484-1491
19. Glueck CJ, Gordon DJ, Nelson JJ, et al. Dietary and other
correlates of changes in total and low density lipoprotein cho-
lesterol in hypercholesterolemic men: the Lipid Clinics Re-
search Program Coronary Primary Prevention Trial. Am J Clin
Nutr 1986;44:489-500
20. Multiple Risk Factor Intervention Trial Research Group. Mul-
tiple Risk Factor Intervention Trial: risk factor changes and
mortality results. JAMA 1982;248:1465-1467
21. Davis BR, Curb JD, Tung B, et al. Standardized physician
preparation of death certificates. Controlled Clin Trials.
1987;8:110-120
22. Hypertension Detection and Follow-up Program Cooperative
Group. The effect of antihypertensive drug treatment on mor-
tality in the presence of resting electrocardiographic abnor-
malities at baseline: the HDFP experience. Circulation 1985;
70:996-1003
23. Curb JD, Hardy RJ, Labarthe DR, Borhani NO, Taylor JO.
Reserpine and breast cancer in the Hypertension Detection and
Follow-up Program. Hypertension 1982;4:307-311