Original article 1015
Low-dose aspirin does not interfere with the blood pressure-
lowering effects of antihypertensive therapy.
Alberto Zanchettia , Lennart Hanssonb , Gastone Leonettia , Karl-Heinz Rahnc ,
Luis Ruiloped , Ingrid Warnolde and Hans Wedelf
Background It has been reported that aspirin (ASA) may
interfere with the blood pressure (BP)-lowering effect of
various antihypertensive agents and attenuate the
beneficial effects of angiotensin-converting enzyme (ACE)
inhibitors in patients with congestive heart failure.
Methods and results Data from the Hypertension Optimal
Treatment (HOT) Study, in which 18 790 intensively treated
hypertensive patients were randomized to either ASA
75 mg daily or placebo for 3.8 years (with a 15% reduction
in cardiovascular events and a 36% reduction in
myocardial infarction in ASA-treated patients), were
reanalysed for the whole group of patients and for various
subgroups with particular attention to the possible effects
of ASA on BP and renal function. In ASA-treated and
placebo-treated patients: (1) systolic blood pressure (SBP)
and diastolic blood pressure (DBP) values achieved with
antihypertensive treatment were superimposable, with
clinically irrelevant differences; (2) these superimposable
SBP and DBP were achieved with antihypertensive
therapies, that were quantitatively and qualitatively similar,
and (3) changes in serum creatinine and in estimated
creatinine clearance and the number of patients
developing renal dysfunction were also similar.
Furthermore, the cardiovascular benefits of ASA were of
the same magnitude in hypertensive patients receiving or
not receiving ACE-inhibitors.
Introduction
It has been reported that aspirin (acetylsalicylic acid,
ASA) and other cycloxygenase inhibitors may interfere
with the blood pressure-lowering effect of angiotensin-
converting enzyme (ACE) inhibitors [1–3], beta-
blockers and diuretics [4], although these reports have
not been fully substantiated by more recent studies [5–
8]. In addition, ASA has been implicated in attenuating
the beneficial effects of ACE inhibitors in patients with
congestive heart failure or after acute myocardial infarc-
tion. In particular, aspirin has been reported to abolish
the peripheral vasodilating activity of ACE inhibitors
[9–11], and to worsen renal function in patients with
congestive heart failure [12,13]. More importantly, a
sub-analysis of the Studies of Left Ventricular Dysfunc-
tion (SOLVD) trial [14] has shown that the prolonga-
tion of survival associated with the use of enalapril was
absent in a subset of heart failure patients taking
aspirin. Similarly, congestive heart failure patients in
0263-6352 & 2002 Lippincott Williams & Wilkins
Conclusions Even long-term, low-dose ASA does not
interfere with the BP-lowering effect of antihypertensive
agents, including combinations with ACE inhibitors, or with
renal function. No negative interaction occurs between
ACE inhibition and the cardiovascular benefits of small
dose of ASA. Our conclusions cannot be extended to larger
doses of ASA, or to patients with congestive heart failure.
J Hypertens 20:1015–1022 & 2002 Lippincott Williams &
Wilkins.
Journal of Hypertension 2002, 20:1015–1022
Keywords: aspirin, angiotensin converting enzyme inhibitors,
antihypertensive therapy
a
Centro di Fisiologia Clinica e Ipertensione, Università di Milano, Ospedale
Maggiore and Istituto Auxologico Italiano, Milano, Italy, b University of Uppsala,
Department of Public Health and Social Sciences, Clinical Hypertension
Research, Uppsala, Sweden, c Westfälische Wilhelm-Universität Münster,
Medizinische Poliklinik, Münster, Germany, d Hypertension Unit, Hospital 12 de
Octubre, Madrid, Spain, e AstraZeneca, Mölndal, Sweden and f Nordic School of
Public Health, Göteborg, Sweden.
Sponsorship: The principal sponsor of the HOT Study was Astra AB, now
AstraZeneca. Local sponsors were Astra Merck Inc., USA, TEVA, Israel and
Hoechst, Argentina.
Correspondence and requests for reprints to Professor A. Zanchetti, Centro di
Fisiologia Clinica e Ipertensione, Università di Milano – Ospedale Maggiore, Via
F. Sforza, 35, 20122 Milano, Italy
Tel: +39 (02) 5501 1295; fax +39 (02) 5518 7506;
e-mail: zanchett@mailserver.unimi.it
Received 3 December 2001 Revised 17 January 2002
Accepted 22 January 2002
the Cooperative New Scandinavian Enalapril Survival
Study (CONSENSUS) II trial who were taking aspirin
had a lower mortality benefit from enalapril than pa-
tients who were not taking aspirin [15]. Consequently,
the question has been raised whether aspirin is safe for
patients with hypertension or heart failure [16], but the
matter remains controversial [17].
The question is not without clinical consequences, not
only for heart failure or post-myocardial infarction
management, but also for antihypertensive treatment,
which in current practice is often associated with
antiplatelet agents.
Information provided by the Hypertension Optimal
Treatment (HOT) Study may help to answer the
question of the possible interference of low-dose ASA
with antihypertensive therapy. This large trial has
randomized 18 790 hypertensive patients, all receiving
1016 Journal of Hypertension 2002, Vol 20 No 5
intensive antihypertensive therapy, to either a 75 mg
daily dose of ASA or placebo, and followed them up,
double-blindly, for an average period of 3.8 years. The
principal results of this trial have shown that ASA
significantly reduces the rate of major cardiovascular
events by 15% and that of myocardial infarctions by
36% [18]. The original paper reported that there was no
significant difference in the reductions in systolic blood
pressure (SBP) and diastolic blood pressure (DBP) and
in the SBP and DBP achieved with antihypertensive
therapy between patients randomized to either ASA or
its placebo [18]. The further analyses of the HOT
Study data presented here were intended to investigate
whether:
(1) the distributions of the SBP and DBP values
achieved with antihypertensive therapy were
superimposable in patients receiving ASA or pla-
cebo;
(2) the blood pressure-lowering effect of antihyper-
tensive therapy differed between patients receiv-
ing ASA or placebo in subgroups of hypertensive
patients with different characteristics or risk pro-
file;
(3) patients treated with ASA had to receive a more
intensive or qualitatively different antihyperten-
sive therapy in order to achieve the same SBP and
DBP;
(4) a possible negative interaction between ASA and
ACE inhibitors resulted in lower benefits of ASA
in patients receiving ACE inhibitors in the anti-
hypertensive regimen;
(5) renal function was differently affected by inten-
sive antihypertensive therapy in patients receiving
ASA or its placebo.
Methods
Study population and design
These have been previously reported in detail [18].
Briefly, the HOT Study included 18 790 hypertensive
patients with baseline DBP between 100 and
115 mmHg. Patients were randomly allocated in a
double-blind way to a low dose, 75 mg daily, of ASA
(Bamycor, AstraZeneca, Södertälje, Sweden) or an
identically-looking placebo tablet. Patients were also
randomly assigned to one of three DBP target groups:
< 90, < 85 and < 80 mmHg, but in the present
analyses the three DBP target groups will be consid-
ered together, and comparison limited to patients
randomized to ASA or to its placebo. The antihyperten-
sive regimen prescribed in the HOT Study protocol in
order to aim at the target DBP consisted of five
successive steps, all based on the long-acting dihydro-
pyridine calcium antagonist felodipine. Step 1: felodi-
pine 5 mg once daily; step 2: addition of a low-dose of
either an ACE inhibitor or a beta-blocker (class and
agent left to the investigator’s choice); step 3: as step 2,
but with felodipine 10 mg once daily; step 4: as step 3,
but with doubling the dose of either the ACE inhibitor
or the beta-blocker (class and agent left to the investi-
gator’s discretion); step 5: addition of a diuretic. On the
whole, about 82% of the patients received a calcium
antagonist, usually felodipine, alone or in com-
bination, 41% received an ACE inhibitor, 28% a beta-
blocker and 22% a diuretic, the last three agents usually
in combination with felodipine or between them [18].
Follow-up
Blood pressure was measured with a tested oscillo-
metric semiautomatic device (Visomat OZ, D2 , Inter-
national, Hestia, Germany) [19]. Blood pressure was
taken three times with the patients seated (and the arm
supported at the heart level) after they had 5 min rest,
at each pre-randomization visit, at randomization,
3 months and 6 months after randomization, and there-
after twice a year; a final visit was made within 1 month
of the termination date.
Cardiovascular events were evaluated by an indepen-
dent clinical event committee blinded to the target
DBP group and the type of treatment (ASA or placebo)
to which the patients had been randomized. Major
cardiovascular events were the sum of all (fatal and
non-fatal) myocardial infarction, all (fatal and non-fatal)
stroke, plus any other cardiovascular death. All myocar-
dial infarction did not include silent myocardial infarc-
tion.
Renal function was evaluated at randomization and at
the end of treatment by serum creatinine concentration,
from which estimated creatinine clearance was calcu-
lated by the Cockcroft and Gault formula [20].
Patients’ stratification
Two types of risk stratification were used: by global
cardiovascular risk [21] and by individual risk factors
[22]. Global risk stratification was done following the
criteria provided by the 1999 World Health Organiza-
tion International Society of Hypertension guidelines
[23]. The numerosity of the various risk groups is
indicated in Table 2. Patients were also stratified on
the basis of the antihypertensive treatment received in:
(1) patients that never received an ACE inhibitor
during the HOT Study, (2) patient that received ACE
inhibitors during the trial, at least at the time of one
visit, (3) patients continuously treated with an ACE
inhibitor after an ACE inhibitor was introduced.
Statistical methods
Blood pressures achieved during treatment in the HOT
treatment population and in each subgroup, separately
for ASA or placebo treatments, were calculated by
averaging all blood pressures measured at each visit,
 Aspirin and antihypertensive therapy Zanchetti et al. 1017

from 6 months (end of titration phase) to end of study
(or appearance of an event). Mean dose step was
calculated by averaging treatment steps at each visit
from 6 months onwards. The use of various classes of
antihypertensive agents was calculated, based on the
use at the final visit, and expressed as percentages.
Comparisons of demographic and baseline character-
istics, baseline and achieved blood pressures, mean
dose steps, percentages of use of different antihyper-
tensive drugs, serum creatinine concentrations and
estimated creatinine clearances, in patients randomized
to either ASA or placebo, were done by t-test, and the
limit for statistical significance was set at the conven-
tional limit of P , 0.05. For comparisons of the effects
of ASA and placebo on major cardiovascular events and
on myocardial infarction in subgoups of patients re-
ceiving or non-receiving ACE inhibitors, a Cox
proportional-hazard model was employed and effects
expressed as relative risk (RR), with 95% confidence
intervals (CI), of having been randomized to ASA or
placebo. RR lower than one indicate that ASA is better,
and 95% CI entirely below or above one indicate a
statistically significant effect (P at least , 0.05).
non-antihypertensive medications, separately for pa-
tients randomized to ASA and for those randomized to
placebo. The two cohorts were perfectly matched.
Baseline characteristics and SBP and DBP values in
patients belonging to different risk subgroups were
reported in two previous papers [21,22]. Within each
subgroup, no baseline characteristics were significantly
different in patients receiving ASA or placebo.
Systolic blood pressure and diastolic blood pressure
achieved by antihypertensive therapy
As previously reported [18], in the overall cohort of
HOT Study patients, there were no differences in
mean achieved SBP and DBP between patients rando-
mized to ASA or placebo (means  SD of all values
measured from 6 months to end of treatment, SBP
141.9  11.7 and 141.3  11.6 mmHg; DBP 83.3  5.3
and 83.0  5.3 mmHg, respectively). Figure 1 shows
that the frequency distribution of DBP and SBP values
throughout the treatment period was also entirely
superimposable in patients randomized to either ASA
or placebo.

We are aware that subgroup and post-hoc analyses have Table 2 (first four columns) gives the means  SD of
a purely descriptive value, and consequently no at- SBP and DBP values throughout the follow-up, from
tempt has been made to correct for multiple testing. end titration to study end, in each of the different
subgroups. As previously reported [21,22], DBP values
Results achieved in different risk subgroups were very similar,
Patient characteristics at randomization with minor differences without clinical significance.
Table 1 shows demographic characteristics, and base- The close similarity of achieved DBP in all subgroups
line values of SBP and DBP, risk factors, previous is likely to result from the fact that DBP was the target
antihypertensive treatment and current treatment with that study investigators had to reach by the treatment
steps. On the other hand, achieved SBP values (that
were not treatment targets) often differed more sub-
Demographic and baseline characteristics of patients
Table 1 stantially between different risk subgroups mostly due
randomized to ASA and placebo: mean (SD) or % to differences in baseline SBP. While the differences in
ASA (n ¼ 9399) Placebo (n ¼ 9391) achieved SBP between patients with or without a given
risk factor were commonly of a small magnitude (from
Men/women (%) 53/47 53/47
Age (years) 61.5 (7.5) 61.5 (7.5)
a few tenths of a mmHg to 5 mmHg), more substantial
Race: Caucasian (%) 93.7 93.0 differences (about 15 mmHg) were found between
Body mass index (kg/m2 ) 28.4 (4.6) 28.4 (4.7) patients with baseline SBP , 160 mmHg or baseline
Diastolic blood pressure (mmHg) 105.5 (3.4) 105.4 (3.4)
Systolic blood pressure (mmHg) 169.6 (14.0) 169.7 (14.3) SBP > 180 mmHg.
S-cholesterol (mmol/l) 6.1 (1.1) 6.1 (1.2)
S-creatinine (ìmol/l) 89 (22) 89 (26)
Smokers (%) 15.9 15.9
Despite these differences between risk subgroups,
Previous MI (%) 1.5 1.5 within each subgroup the achieved SBP and DBP
Previous stroke (%) 1.2 1.2 values of patients randomized to either ASA or placebo
Other previous CHD (%) 5.9 6.0
Diabetes mellitus (%) 8.0 8.0 only showed tiny differences, mostly of a few tenths of
Obstructive lung disease (%) 2.7 3.1 a mmHg. Although the very small blood pressure
Previous treatment (%) 52.5 52.6 differences between ASA and placebo patients seen in
Current medication:
Antiarrhythmic agents (%) 0.8 1.1 the overall cohort of HOT Study patients (SBP
Digitalis (%) 2.0 2.0 0.6 mmHg and DBP 0.3 mmHg higher in ASA patients)
Lipid-lowering agents (%) 6.9 7.3
NSAID (%) 6.6 6.4
were consistently found in all subgroups, the smallness
Other analgesics (%) 3.2 3.5 of these differences, in front of SBP/DBP reductions of
Steroids (%) 1.4 1.2 28/22 mmHg, indicate that, if low-dose ASA exerts
ASA, aspirin; MI, myocardial infarction; CHD, coronary heart disease; NSAID, some interference with the effects of antihypertensive
non-steroid anti-inflammatory drugs. therapy, this interference is of no clinical significance.
1018 Journal of Hypertension 2002, Vol 20 No 5
Fig. 1
25
20
15
Frequency (%)
10
0
60 70 80 90 100 110 120
Achieved DBP and SBP (mmHg)
Frequency distribution of systolic blood pressure (SBP) and diastolic blood pressure (DBP) values achieved by treatment during the Hypertension
Optimal Treatment (HOT) Study (means of values at each visit from 6 months to study end) in all patients randomized to asprin (ASA) (filled
symbols) and in all those randomized to placebo (open symbols).
Antihypertensive treatment intensity and antihypertensive
agents used in patients randomized to either ASA or
placebo
Table 2 (middle columns) shows that the substantially
similar SBP and DBP values in ASA and placebo
patients were obtained by the same intensity of anti-
hypertensive treatment, as measured by the mean of
the steps of the protocol regimen at all visits subse-
quent to titration end. As previously reported [21,22],
treatment intensity was often different in subgroups
with or without a given risk factor, the treatment step
being generally (though not invariably) higher in the
presence of a risk factor, but even in these patient
subgroups ASA and placebo patients received the same
average intensity of antihypertensive treatment. Table
2 (last eight columns) indicate the percentage use of
different classes of antihypertensive agents. All drug
classes were given to patients randomized to ASA or
placebo in the same proportions, without any systema-
tic trend of a more frequent use of any drug class in
patients randomized to ASA.
130 140 150 160 170 180 190 200
Cardiovascular benefits of ASA in patients receiving or not
receiving an ACE inhibitor in the antihypertensive
treatment regimen
Tables 3 and 4 indicate the incidence of major cardio-
vascular events and of myocardial infarction in patients
never receiving an ACE inhibitor, or receiving an ACE
inhibitor at least during some part of the trial or con-
tinuously during the trial. Both among placebo patients
and among patients receiving ASA the event rates were
similar in subgroups with or without ACE inhibitors
though regularly lower in ASA than placebo patients.
ASA significantly reduced the rate of myocardial infarc-
tions, independently of the use or not of ACE inhibitors.
Although the 95% confidence intervals of the relative
risks in the three subgroups largely overlapped, the risk
reductions induced by ASA were, if any, larger in patients
receiving ACE inhibitors (ÿ50 and ÿ61%) than in those
never treated with an ACE inhibitor (ÿ38%).
Renal effects of acetylsalicylic acid
Table 5 reports changes in serum creatinine and in
Table 2 Mean blood pressure values, mean dose titration step (mean 6 months to the end of the study) and drug class used at the final visit
Drug class used at the final visit (%)

Mean SBP Mean DBP Mean treatment step Calcium antagonist ACE inhibitors Beta-blockers Diuretics

Patient group n ASA pl ASA pl ASA pl ASA pl ASA pl ASA pl ASA pl

High–very high risk 9390 144.1 (12.5) 143.7 (12.3) 83.4 (5.6) 83.0 (5.5) 2.6 2.6 84 84 45 44 29 28 24 24
Medium risk 9400 139.6 (10.4) 139.0 (10.3) 83.2 (5.1) 82.9 (5.0) 2.3 2.3 82 80 36 38 28 27 19 20
Diabetes 1501 146.4 (11.9) 145.5 (11.0) 83.1 (5.5) 82.7 (5.2) 2.5 2.6 84 86 47 48 25 23 23 26
No diabetes 17 289 141.5 (11.6) 141.0 (11.6) 83.3 (5.3) 83.0 (5.3) 2.4 2.4 83 82 40 41 29 28 21 22
IHD 3080 145.0 (12.0) 143.7 (11.4) 83.2 (5.2) 82.8 (5.2) 2.6 2.6 84 84 43 43 31 30 24 25
No IHD 15 710 141.3 (11.6) 140.9 (11.6) 83.3 (5.4) 83.0 (5.3) 2.4 2.4 83 82 40 41 28 27 21 22
Smoking 2983 141.3 (11.7) 141.2 (11.5) 83.0 (5.3) 82.9 (5.0) 2.5 2.5 88 85 40 40 28 28 18 18
No smoking 15 807 142.0 (11.7) 141.4 (11.6) 83.4 (5.3) 83.0 (5.3) 2.4 2.4 82 82 40 41 29 28 22 23
S-cholesterol . 6.8 mmol/l 4380 143.2 (11.4) 142.6 (11.8) 83.7 (5.3) 83.1 (5.2) 2.4 2.4 82 80 38 38 31 31 22 22
S-cholesterol < 6.8 mmol/l 14 225 141.5 (11.8) 140.9 (11.5) 83.2 (5.3) 82.9 (5.3) 2.5 2.5 83 83 41 42 28 27 21 22
S-creatinine . 115 ìmol/l 1367 140.6 (12.9) 140.2 (11.9) 82.8 (5.4) 82.6 (5.3) 2.7 2.7 83 83 48 45 26 30 24 27
S-creatinine < 115 ìmol/l 17 230 142.0 (11.6) 141.4 (11.5) 83.3 (5.3) 83.0 (5.2) 2.4 2.4 83 82 40 41 29 28 21 22
Men 9907 140.8 (11.6) 140.4 (11.5) 83.5 (5.4) 83.2 (5.3) 2.6 2.6 85 85 44 45 28 27 21 21
Women 8883 143.1 (11.7) 142.4 (11.5) 83.0 (5.2) 82.7 (5.2) 2.3 2.3 81 79 36 37 29 29 22 24
Older (> 65 years) 5987 145.5 (11.6) 144.9 (11.6) 82.4 (5.1) 82.0 (5.1) 2.3 2.3 82 82 39 39 24 23 22 21
Younger (, 65 years) 12 803 140.2 (11.4) 139.7 (11.2) 83.7 (5.4) 83.4 (5.3) 2.5 2.5 83 82 41 42 31 30 21 22
SBP (> 180) 4114 149.8 (11.7) 149.0 (11.6) 83.2 (5.7) 82.8 (5.5) 2.6 2.6 85 85 44 42 32 29 24 26
SBP (160–, 180) 10 001 142.0 (10.4) 141.4 (10.3) 83.3 (5.2) 83.0 (5.3) 2.4 2.4 83 83 39 40 29 27 22 22
SBP (, 160) 4675 134.8 (9.8) 134.4 (9.5) 83.4 (5.2) 83.1 (5.0) 2.4 2.4 81 79 40 43 26 27 19 20
DBP (> 107) 5854 142.7 (12.3) 142.2 (12.2) 84.4 (5.8) 84.0 (5.7) 2.8 2.8 84 84 45 46 35 32 26 27
DBP (104–, 107) 5590 141.9 (11.4) 141.4 (11.5) 83.2 (5.1) 82.8 (5.0) 2.4 2.4 84 83 39 40 29 27 20 21
DBP (, 104) 7346 141.2 (11.4) 140.6 (11.1) 82.5 (4.9) 82.3 (5.0) 2.2 2.2 81 81 38 39 23 25 18 19
All patients 18 790 141.9 (11.7) 141.3 (11.6) 83.3 (5.3) 83.0 (5.3) 2.4 2.4 83 82 40 41 29 28 21 22

ASA, aspirin; SBP, systolic blood pressure; DBP, diastolic blood pressure; pl, placebo; IHD, ischemic heart disease.
Aspirin and antihypertensive therapy Zanchetti et al.
1019
1020 Journal of Hypertension 2002, Vol 20 No 5

Table 3Major cardiovascular events in the ASA-treated patients compared with placebo-treated patients for patients never treated with
ACE inhibitors and patients treated with ACE inhibitors (two definitions)
Major cardiovascular events

ASA Placebo

Patients Events/1000 Events/1000 Relative 95% Confidence

Additional therapy (n) n patient years n patient years risk interval P

Patients never treated with ACE inhibitor 9182 131 7.5 162 9.5 0.79 0.63–0.99 0.04
Patients treated with ACE inhibitor at least 9142 126 8.8 146 10.1 0.87 0.69–1.11 0.26
during some part of the follow-up
Patients continuously treated with ACE inhibitor 6972 88 8.2 106 9.7 0.85 0.64–1.12 0.24
after first additiony

 Patients on ACE inhibitors at least when leaving one visit during the follow-up in the HOT Study. Start of comparison: First visit on ACE inhibitor. y Patients continuously
on ACE-inhibitors after first visit on ACE inhibitor. Start of comparison: first visit on ACE inhibitor. ACE, angiotensin converting enzyme; ASA, aspirin.

Table 4 All myocardial infarction in the ASA-treated patients compared with placebo-treated patients for patients never treated with ACE
inhibitors and patients treated with ACE inhibitors (two definitions)
All myocardial infarction

ASA Placebo

Patients Events/1000 Events/1000 Relative 95% Confidence

Additional therapy (n) n patient years n patient years risk interval P

Patients never treated with ACE inhibitor 9182 29 1.6 46 2.7 0.62 0.39–0.98 0.04
Patients treated with ACE inhibitor at least 9184 26 1.8 53 3.6 0.50 0.31–0.79 0.003
during some part of the follow-up
Patients continuously treated with ACE inhibitor 7006 14 1.3 37 3.3 0.39 0.21–0.71 0.002
after first additiony

 Patients on ACE inhibitors at least when leaving one visit during the follow-up in the HOT Study. Start of comparison: first visit on ACE inhibitor. y Patients continuously
on ACE-inhibitors after first visit on ACE inhibitor. Start of comparison: first visit on ACE inhibitor. ACE, angiotensin converting enzyme; ASA, aspirin.

estimated creatinine clearance, and the number of
patients with worsened renal function separately for all
patients randomized to ASA or to placebo. The use of
ASA did not appear to have influenced any of the
parameters of renal function investigated in the HOT
Study, or the number of patients whose renal function
worsened during the study [24]. Table 5 also reports
changes in renal function in the subset of patients with
higher serum creatinine at baseline (. 115 ìmol/l), who
may have been more prone to renal impairment by
ASA. Even in these patients, there were no significant
differences in renal function changes or in the number
of patients with worsened renal function between
subjects randomized to ASA or placebo.
Discussion
The detailed data presented in this paper rule out the
possibility that co-administration of low-dose ASA may
interfere in a clinically relevant way with the blood
pressure-lowering effects of the antihypertensive agents
used in the HOT Study. The SBP and DBP values
achieved, the intensity of the antihypertensive regimen,
and the number and type of drug used were entirely
similar in ASA and placebo patients, not only in the
overall HOT Study population, but in all subgroups in
which this population was subdivided. The clinical
relevance of the findings here reported is based on the
fact that in the HOT Study, antihypertensive drugs
and ASA were given in doses of demonstrated clinical
usefulness (marked and persistent reduction of blood
pressure to target values for antihypertensive agents,
significant prevention of myocardial infarction for ASA),
for a prolonged treatment period (average 3.8 years), to
a very large number of patients (18 790). Furthermore,
the HOT Study used four major classes of antihyper-
tensive agents (calcium antagonists, ACE inhibitors,
beta-blockers and diuretics) and, therefore, the conclu-
sions of this paper extend to all these major classes of
drug, particularly when given in combination.
Other recent studies have denied that ASA, at least at
low dose, blunts the antihypertensive or vasodilating
actions of ACE inhibitors or angiotensin II receptor
antagonists [5–8]. These reports are strongly supported
by data from the HOT Study, the conclusions of which
are also based on the analysis of various subgroups of
hypertensive patients with different baseline character-
istics and risk factors.
In addition, our data do not support the possibility that
low-dose ASA may reduce the effectiveness of antihy-
pertensive therapy in preventing the occurrence of
 Aspirin and antihypertensive therapy Zanchetti et al. 1021

major cardiovascular events and, particularly, myocar-

0.056

0.62
0.11

0.50

0.64

0.20
0.96
dial infarction. The magnitude of the relative benefit of

M (SD), Means and standard deviations at B, baseline; E, end treatment; ˜, difference E–B. Only patients with S-creatinine measured at baseline and at final visit. Worsening renal function, numbers (n) of patients with S-
ASA in the treated hypertensive patients of the HOT
Study (an average reduction of 36% in myocardial
infarction) is of the same magnitude as that reported in

ÿ13.28 (77.44)
58.60 (18.52)
140.75 (47.47)
127.47 (75.76)

70.78 (28.74)
12.18 (20.73)
other recent studies in which patients did not system-
Patients with baseline S-creatinine .115 ìmol/l

M (SD)

32
atically receive antihypertensive therapy [25,26]. Fur-
Placebo

thermore, the benefits of ASA were separately analyzed

in several subgroups of HOT Study patients, and in no
subgroup the rate of cardiovascular events was higher
556 among ASA than among placebo patients (paper in
556
556
556

556
556
556
n

preparation). Finally, as it is interference of ASA with

ACE inhibitors that has often been implicated, we have
shown that ASA was at least equally beneficial in
preventing myocardial infarctions in patients that were
59.31 (17.04)
136.31 (26.82)
121.11 (54.45)
ÿ15.21 (53.57)

71.55 (27.03)
12.24 (20.11)
M (SD)

never treated with ACE inhibitors, as in patients that

22

had received ACE inhibitors for some part or for most

ASA

of the treatment period. Even for major cardiovascular

events taken together, the order of magnitude of the
benefits of ASA was similar in patients receiving or not
receiving ACE inhibitors.
562
562

562

562
562

562
562
n

The analyses presented in this paper also show that,

even long-term, low-dose ASA does not negatively
0.07
0.69

0.10

0.79
0.26

0.06
0.34
P

interfere with renal function, and that this is also true

in hypertensive patients who already have some degree
of renal dysfunction before initiation of treatment.
88.93 (23.96)
89.54 (29.88)

84.90 (26.29)

84.95 (26.95)
0.62 (27.76)

0.05 (18.52)
M (SD)

Obviously, our conclusions only regard the effects of

51

low-dose ASA, and we cannot exclude that larger doses

Placebo

of ASA, such as those used in several other studies,

may interfere with the blood pressure-lowering effects
of some antihypertensive agents, a possibility supported
All patients

by some evidence recently provided by Guazzi et al [5].

7791
7791

7789
7791

7789
7789
7789
n

Also in our analyses, the consistency by which ASA

creatinine increase > 30% and end treatment S-creatinine >176 ìmol/l. ASA, aspirin.

patients achieved SBP and DBP values a few tenths of

a mmHg higher than placebo patients suggests that
88.31 (20.95)
89.37 (26.96)

85.58 (26.58)
1.06 (16.47)

85.07 (26.65)
ÿ0.51 (18.78)

even low-dose ASA may have some effect, admittedly

Renal effects of randomization to either ASA or placebo

M (SD)

of no clinical relevance, on the results of antihyperten-

41

sive therapy. More relevant effects, however, might be

induced by larger ASA doses. As the HOT Study has
ASA

clearly shown that low-dose ASA is capable of produ-

cing the expected reduction in myocardial infarction in
hypertensive patients, there is no foreseeable reason
7810
7810
7810
7807

7807
7807
7807
n

why larger ASA doses should be administered to hyper-

tensive patients for primary cardiovascular prevention.

A final word of caution should be given in underlining

˜

˜
B

B
E

that our conclusions concern the use of ASA in hyper-

Estimated creatinine clearance

tensive patients, and cannot exclude any untoward

Worsened renal function (n)

reaction to ASA, even in small doses, in patients with

congestive heart failure [16,17].
S-creatinine (ìmol/l)

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