See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/23416333

Interaction between antihypertensives and NSAIDs in primary care: A

controlled trial

Article  in  The Canadian journal of clinical pharmacology = Journal canadien de pharmacologie clinique · September 2008
Source: PubMed

CITATIONS READS

79 2,364

4 authors:

Ivancica Pavlicevic Marion Tomicic

University of Split, Medical School University of Split
40 PUBLICATIONS   169 CITATIONS    28 PUBLICATIONS   177 CITATIONS   

SEE PROFILE SEE PROFILE

Mirjana Rumboldt Zvonko Rumboldt

University of Split Split University School of Medicine
58 PUBLICATIONS   418 CITATIONS    218 PUBLICATIONS   5,658 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Inter Heart 2 View project

ProHealth-Professionalism in Health Care (Project Leader Prof. Ana Marušić) View project

All content following this page was uploaded by Marion Tomicic on 18 May 2014.

The user has requested enhancement of the downloaded file.

 INTERACTION BETWEEN ANTIHYPERTENSIVES AND NSAIDS IN PRIMARY CARE:
A CONTROLLED TRIAL

Ivančica Pavličević, Marion Kuzmanić, Mirjana Rumboldt, Zvonko Rumboldt

Split University School of Medicine, Split, Croatia

Corresponding Author: [email protected]

______________________________________________________________________________________
ABSTRACT

Background
Non-steroidal anti-inflammatory drugs (NSAIDs) may increase blood pressure (BP) and blunt the effects
of many antihypertensives. It seems that NSAIDs and the antihypertensive drugs differ in their propensity
to such an interaction.

Objectives
To determine the extent of the interaction between two antihypertensives and three NSAIDs.

Methods
A prospective clinical trial in a family practice included 88 treated hypertensives aged over 55 years; 39
controls and 49, also taking NSAIDs for osteoarthritis. During this 3-month study, two antihypertensives,
lisinopril/hydrochlorothiazide and amlodipine, were compared with three NSAIDs: ibuprofen,
acetaminophen, and piroxicam. BP was measured with standard mercury sphygmomanometer and with an
automatic device, in standing, sitting, and supine position.

Results
The average starting blood pressure in the study group was 149.3±9.8/88.6±6.8 mm Hg. In the
lisinopril/hydrochlorothiazide subgroup, both ibuprofen and piroxicam elevated systolic BP by 7.7-9.9%
(p<0.001), which, during the acetaminophen period, decreased by 6.9-9.4% to 0.3-0.9% above baseline
(p<0.001), increasing again by 7.0-7.7% (p<0.001) during the second exposition to these drugs. In the
amlodipine subgroup, ibuprofen or piroxicam increased BP by 1.1-1.6% (p>0.290) only, and there were
no significant shifts in the follow-up periods. Analogous deviations were observed with both
measurement devices, in all the examinee’s positions. In the control group, BP did not change
appreciably.

Conclusions
Piroxicam and ibuprofen markedly blunt the effects of antihypertensive drugs while acetaminophen is
almost inert. Lisinopril/hydrochlorothiazide combination is much more affected by this interaction than
amlodipine (ClinicalTrials.gov #NCT00631514).

Key words: Antihypertensive drugs; family practice; interaction; non-steroidal anti-inflammatory drugs

(see Editorial letter Can J Clin Pharmacol Vol 15(3) Fall 2008:e383-e384; October 24, 2008)
__________________________________________________________________________________

A rterial hypertension is the most important

preventable cause of premature death and
disability. Although its treatment is very effective
ription) and interferences (untoward life style,
comedication with prohypertensive agents,
pharmacokinetic and/or pharmacodynamic drug
and well tolerated, the practical achievements leave interactions).1 Indeed, the blood pressure control
much to be desired for two main reasons: inadequate may be markedly blunted by concomitant intake
medication (noncompliance, inappropriate presc- of prohypertensive drugs, such as cocaine,

Can J Clin Pharmacol Vol 15 (3) Fall 2008:e372-e382; October 24, 2008 e372
©2008 Canadian Society for Pharmacology and Therapeutics. All rights reserved.
Interaction between antihypertensives and NSAIDs in primary care: a controlled trial

cyclosporine or erythropoietin, but of major controlled trial in a primary care (family practice)
concern is coprescription of NSAIDs, since the office in Split, Croatia, taking care of some 1,600
interactive potential of these two drug classes is adult patients.
huge due to high prevalence of both hypertension
and osteoarthritis: such a comorbidity is seen in MATERIALS AND METHODS
15-26% of elderly patients from different
populations.1 This factorial, parallel group, prospective study
The prohypertensive effects of NSAIDs enrolled already treated hypertensives (taking
presumably depend on several mechanisms. Their amlodipine or lisinopril/hydrochlorothiazide fixed
analgesic and antiinflammatory effects are mostly combination) of either gender, aged >55 and <76
derived from cyclooxygenase (COX) inhibition years. Informed consent was obtained and the
and consequent decrease in prostaglandin Split University School of Medicine Ethical
synthesis. There are at least two, genetically, Committee approved the study. The investigation
functionally and structurally different moieties of was registered with ClinicalTrials.gov and received
this enzyme: constitutive (COX-1) and inducible PRS #NCT00631514.
(COX-2). COX-1 is permanently active in many The intervention group included persons with
bodily structures, regulating normal tissue concomitant osteoarthritis of the hip or knee,
activities, while COX-2 is activated by requiring regular intake of NSAIDs (at least one
inflammation, trauma or infection. Its inhibition defined daily dose per day in the preceding
leads to decreased PGI2 production in the vascular month). The control group included hypertensive
endothelium, with no change in TxA2 synthesis in patients with the same demographic
the platelets, predisposing to vasoconstriction, characteristics, but not requiring NSAIDs (Table
thrombosis and endothelial lesion. Moreover, all 1). Patients unable to tolerate withdrawal of their
NSAIDs impede physiological prostaglandin osteoarthritis therapy, those unwilling to
synthesis in the kidneys resulting in fluid retention participate and uncooperative persons were not
and local vasoconstriction.1 included. Following clinical work-up and
For all NSAIDs, a more or less pronounced discontinuation of NSAIDs for at least 3 days (the
prohypertensive effect has been described in many run-in period lasted 3-7 days only), the examinees
interventional and observational studies4-19, in with osteoarthritis already taking amlodipine (5-
meta-analyses20-22, and in review papers23-29 (for 10 mg o.d.) or lisinopril/hydrochlorothiazide fixed
the sake of brevity quoted are just the most drug combination (10/6.25-20/12.5 mg o.d.) were
prominent out of more than 100 references). From randomized (sealed envelopes containing
this heterogeneous data (the studies were advanced drug prescription) into two experimental
prospective and retrospective, with highly variable arms, to take either ibuprofen (400-600 mg t.i.d.)
numbers of examinees, with or without placebo or piroxicam (10-20 mg o.d.) for one month,
control, parallel or crossover etc.) a vague followed by acetaminophen (1000 mg t.i.d.)
conclusion results that, among the during the second month as a “wash-out” interval,
antihypertensive agents, calcium channel blockers and resuming the assigned NSAID (ibuprofen or
could be less susceptible to this untoward piroxicam) during the third month of the study
interaction than diuretics, beta-adrenergic (Figure 1). The control examinees (hypertensives
blockers or ACE inhibitors8- 10,15,17, and that some with no osteoarthritis) continued with their current
NSAIDs could be more prohypertensive antihypertensive therapy. That group was included
(ibuprofen, indomethacin, naproxen, piroxicam, to identify and adjust for possible confounding
rofecoxib) than others (acetaminophen, variables (e.g., seasonal variations in ambient
acetylsalicylic acid, celecoxib, ketoprofen, temperature or in salt ingestion).
sulindac).3-8,11-17,20-29 In other words, each patient in the
To test the hypothesis that some NSAIDs are intervention group underwent 3 study periods
more prone to elevate blood pressure than the (phases) of 1 month duration each, taking the
others, and that some antihypertensives are more allotted antihypertensive all the time but switching
susceptible, and others more resistant to this from the assigned NSAID after the first phase to
interaction, we have designed a prospective, acetaminophen during the second phase and
e373 Can J Clin Pharmacol Vol 15 (3) Fall 2008:e372-e382; October 24, 2008
©2008 Canadian Society for Pharmacology and Therapeutics. All rights reserved.
Interaction between antihypertensives and NSAIDs in primary care: a controlled trial

resuming the first NSAID in the third phase. Since orthostatic hypotension, particularly troublesome
the formulations of the study drugs were not in an elderly, friable person (all our patients were
identical, and the dosages were different, it was a over 55 years of age), and the mercury device is
single blind study, in which the assessor physician still the clinical standard, especially in family
(I.P.) was unaware of the patients’ allocation, practice.
performed by the assigner physician (M.K.). Additional measurements were performed
In addition to general demographic (e.g., body weight, serum creatinine, sodium and
quantification, arterial pressure was measured in potassium; 24 h urinary sodium), which will not
the morning, between 9 and 10 a.m., with the be considered in detail in this report. Expecting a
standard mercury sphygmomanometer according minimal relevant difference of 8 mm Hg in
to standard recommendations, registering the systolic blood pressure between the more
mean of the last two of three consecutive readings “prohypertensive” NSAIDs (piroxicam, ibuprofen)
in the supine, sitting and standing position, and and more inert agents in this respect
with the automated blood pressure recorder Model (acetaminophen), and accepting a two-sided α
BPM-100, “VSM MedTechLtd.” (Vancouver, error of 0.05, we had to enroll at least 20
Canada), taking the mean of the last five of six examinees per group to achieve a power of 80%.
consecutive readings in seated position obtained The results are presented as means, standard
in 5 min intervals over 30 min, at the inception deviations (SD) and 95% confidence intervals
(phase 0; baseline), and at the end (i.e. on one of (CI.95 ); statistical significance was assessed using
the period’s last two mornings) of the first (phase analysis of variance (ANOVA), unpaired t test or
2
I), of the second (phase II), and of the third study χ test, as appropriate, employing the SPSS
month (phase III). software package, version 11.5 (SPSS, Chicago,
Standing blood pressure recorded with the Illinois). The p values were corrected for multiple
mercury instrument was designated as the primary testing with the Bonferroni adjustment; a p value
outcome of the trial because taking blood pressure <0.05 was regarded as significant.
in the erect position best detects the undesired

TABLE 1 Baseline characteristics of the examinees

Study group Control Control Intervention Intervention Intervention Intervention

Parameter L/H AM L/HIB L/HPX AM±IB AM±PX
Randomized 22 17 15 14 11 9
(n)
Male/female 12/10 10/7 7/8 5/9 2/9 2/7
(n)
Age (years; 68.3±5.5* 68.7±8.2 70.57.2 69.97.6 69.66.3 69.48.8
mean ±SD)
Weight (kg; 82.111.6 81.7±14.2 84.415.7 78.112.6 80.113.9 87.316.7
mean ±SD)
Standing 149.511.4 147.0±9.9 144.99.3 148.9 13.0 152.96.5 153.15.8
systolic BP
(mm Hg)
Standing 90.08.3 89.5±5.6 87.76.7 88.95.4 87.69.2 90.46.4
diastolic BP
(mm Hg)
*Means standard deviations of the data
Acronyms: AM= amlodipine; IB= ibuprofen; L/H= lisinopril/hydrochlorothiazide; PX= piroxicam.

Can J Clin Pharmacol Vol 15 (3) Fall 2008:e372-e382; October 24, 2008 e374
©2008 Canadian Society for Pharmacology and Therapeutics. All rights reserved.
Interaction between antihypertensives and NSAIDs in primary care: a controlled trial

FIG. 1 Flowchart showing the study inclusions, exclusions and final sample size

Hypertensive persons aged 55-76 years

N=223

With OA Without OA
N=85 N=138

Consented to participate

N=64 N=59

Enrolled

N=49 N=39

Randomized

N=15 N=14 N=11 N=9 Continued on the

Phase I L/H+IB L/H+PX AM+IB AM+PX same regimen
Phase II L/H+AC L/H+AC AM+AC AM+AC N=39
Phase III L/H+IB L/H+PX AM+IB AM+PX

AC= acetaminophen; AM= amlodipine; IB= ibuprofen; L/H= lisinopril/hydrochlorothiazide; OA= osteoarthritis;
PX= piroxicam.
None of the randomized subjects was lost to follow-up, and all 88 were analysed.

RESULTS the inception of this study was 148.6±10.6 /

89.2±7.1 mm Hg; 22 (56.4%) of the control subjects
There were all in all 88 examinees; 38 males were taking lisinopril/hydrochlorothiazide, and 17
(43.2%) and 50 females (56.8%), 49 of whom (43.6%) amlodipine only.
(55.7%) were in the intervention, and 39 (44.3%) The intervention group patients were
in the control groups. In the control group there allocated in 4 subgroups: 15 (30.6% of them)
were 17 women and 22 men, aged 68.5±6.7 years, were taking lisinopril/hydrochlorothiazide with
weighting 82.0±12.4 kg, and their standing BP at ibuprofen, and 14 (28.6%) with piroxicam; 11
e375 Can J Clin Pharmacol Vol 15 (3) Fall 2008:e372-e382; October 24, 2008
©2008 Canadian Society for Pharmacology and Therapeutics. All rights reserved.
Interaction between antihypertensives and NSAIDs in primary care: a controlled trial

(22.4%) were taking amlodipine with ibuprofen, 1490429 mg for acetaminophen; the individual
and 9 (18.4%) with piroxicam. doses were held constant during the study.
The mean age of the intervention group Standing systolic blood pressure (SBP)
(Table 1) was 69.86.9 years; 69.4 7.2 for the variations during this study are shown in Table 2.
female, and 70.16.8 years for the male The observed differences in the control group did
examinees, not differing significantly between the not reach statistical significance during the study
subgroups or towards the control group (one-way (ANOVA: F3,63= 0.061; p= 0.980), while in the
ANOVA: F5,82=0,220; p=0.95 and F1,86=0.043, intervention group, there were several substantial
p=0.83, respectively). The average sitting blood changes. In the lisinopril/hydrochlorothiazide
pressure, 148.910.2 / 89.16.9 mm Hg, did not subgroup assigned to ibuprofen, there were
differ significantly between the study subsets significant between-phase deviations (ANOVA:
(ANOVA: F1,86=1.982; p=0.142). The same was F3,42=7.710; p<0.001; 2= 0.355). The average
true for the average heart rate (75.29.3 bpm), baseline SBP in phase I increased by 7.7% (+11.2
body weight (81.813.0 kg), serum creatinine mm Hg; CI.95 6.1-16.5 mm Hg; p=0.004),
(92.820.2 µmol), serum potassium (4.540.48 decreased in phase II by 6.9% (-10.8 mm Hg; CI.95
mmol/l) or 24 h urinary sodium excretion 5.2-16.4 mm Hg; p=0.013), and increased again in
(189.386.6 mmol). The average daily drug phase III by 6.7% (+9.7 mm Hg; CI.95 3.3-16.2
dosages were 18.04.5/11.32.8 mg for mm Hg; p= 0.051). A significant interaction effect
lisinopril/hydrochlorothiazide combination, between the study phase and experimental
subgroup (ANOVA: F2, 68 = 3.770; p= 0.028;
6.92.4 mg for amlodipine, 1154348 mg for
ibuprofen, 16.94.8 mg for piroxicam, and 2 =0.1) was found.

TABLE 2 Standing systolic blood pressure changes during the study periods

Period Control Control Intervention Intervention Intervention Intervention

L/H AM L/HIB L/H±PX AM±IB AM±PX
Phase 0 149.511.4 147.0±9.9 144.99.3 148.913.0 152.96.5 153.15.8
(baseline)
Phase I 149.414.9 147.2±13.2 156.112.6 * 162.917.6 ** 155.37.1 154.89.2
Phase II 148.514.6 149.2±12.9 145.314.7 147.614.6 155.69.6 153.28.7
Phase III 149.111.5 146.8±12.8 155.012.9 160.414.8 * 151.75.0 152.012.0
Means standard deviations of the data
*p = 0.021 – 0.040; **p = 0.001 – 0.020
Acronyms: AM= amlodipine; IB= ibuprofen; L/H= lisinopril/hydrochlorothiazide; PX= piroxicam.

In the lisinopril/hydrochlorothiazide subgroup control group were tiny (ANOVA: F3,63= 0.061; P=
assigned to piroxicam, the same changes were 0.980).
even more pronounced and the between-phase The calcium channel blocker subgroups did
deviations were highly significant (ANOVA: F3,36= not show such outcomes. In the amlodipine
9.986; p<0.001; 2= 0.454). The average SBP in examinees assigned to ibuprofen, the between-
phase I increased by 9.5% (+14.1 mm Hg; CI.95 phase blood pressure deviations were minor
6.6-20.8 mm Hg; p= 0.001), decreased in phase II (ANOVA: F3,27= 1.303; p=0.294), and the
by 9.4% (-13.3 mm Hg; CI.95 7.0-20.3 mm Hg; p= differences between the intervention and the
0.004), and increased again in phase III by 8.0% control group were insignificant (ANOVA: F2,46=
(+9.7 mm Hg; CI.95 5.2-14.5 mm Hg; p=0.030). 0.883; p= 0.421). The increase in SBP between
Taking these two subgroups together, the phase 0 and phase I was 1.5% (+2.4 mm Hg; CI.95
global effect of ibuprofen or piroxicam addition ranging from -4.9 to +10.3 mm Hg). In the
was even stronger (ANOVA: F3,81= 18.058; amlodipine subgroup randomized to piroxicam,
P=0.003; 2 = 0.401), while SBP changes in the the between-phase deviations were even less

Can J Clin Pharmacol Vol 15 (3) Fall 2008:e372-e382; October 24, 2008 e376
©2008 Canadian Society for Pharmacology and Therapeutics. All rights reserved.
Interaction between antihypertensives and NSAIDs in primary care: a controlled trial

(ANOVA: F3,24= 0.206; p= 0.891), insignificant in did not fluctuate significantly in the control group
comparisons with the control group (ANOVA: (ANOVA: F3,48= 2.039; p= 0.121).
F2,44= 0.257; p=0.774), and did not change during In the lisinopril/hydrochlorothiazide
the acetaminophen interval. Comparing both subgroup randomized to ibuprofen, significant
lisinopril/hydrochlorothiazide subgroups taking between-phase variations were noted (ANOVA:
either ibuprofen or piroxicam (n=29) to those F3,42=10.403; p<0.001; 2= 0.426): an increase in
taking amlodipine under the same conditions phase I by 8.6% (+7.6 mm Hg; CI .95 2.2-13.4 mm
(n=20), the observed differences were remarkable Hg; p= 0.022), a decrease in phase II by 7.0%
(e.g. t-test in period II: t=2.605; CI .95 =1.815- (-6.7 mm Hg; CI .95 1.9-11.7 mm Hg; p= 0.027),
14.18; df 47; p=0.0123). and another increase in phase III by 6.4% (+5.7
Similar results were obtained with the mm Hg; CI.95 1.8-9.4 mm Hg; p= 0.031).
diastolic blood pressure (DBP; Table 3), which

TABLE 3 Standing diastolic blood pressure changes during the study periods

Period Control Control Intervention Intervention Intervention Intervention

L/H AM L/H±IB L/H±PX AM±IB AM±PX
Phase 0 90.08.3 89.5±5.6 87.76.7 88.95.4 87.69.2 90.46.4
(baseline)
Phase I 90.97.7 90.2±7.1 95.36.6 ** 95.89.9* 86.87.7 92.18.8
Phase II 89.48.8 92.8±8.1 88.67.5 89.610.4 86.59.7 91.98.3
Phase III 92.37.1 89.4±8.0 94.39.1 ** 95.411.4 89.48.3 92.87.3
Means standard deviations of the data
*p = 0.021 – 0.040; **p = 0.001 – 0.02
Acronyms: AM= amlodipine; IB= ibuprofen; L/H= lisinopril/hydrochlorothiazide; PX= piroxicam.

The mean DBP among the lisinopril/ F3,78=14.633; p<0.001; 2 = 0.360) than in the
/hydrochlorothiazide examinees assigned to amlodipine group (ANOVA: F3,45= 0.757; p=
piroxicam showed similar variations (ANOVA: 0.524). DBP differences between the two
F3,33=4.448; p=0.010; 2 = 0.288); it increased in lisinopril/hydrochlorothiazide subgroups taking
phase I by 7.0% (+6.2 mm Hg; CI.95 2.5-9.9 mm NSAIDs were minor (ANOVA: F2,80= 0.205; P=
Hg; p=0.025), decreased in phase II by 5.4% (- 0.815).
5.2 mm Hg; CI .95 1.3-9.3 mm Hg; p=0.039), and Comparable blood pressure changes were
increased again in phase III by 5.3% (+5.8 mm observed in the supine and sitting position (not
Hg; CI.95 1.9-9.4 mm Hg; p=0.042). DBP shown), and with automatic blood pressure
variability in the amlodipine group was minor recording (Table 4). Automated readings, less
(ANOVA: F3,30= 1.891; p= 0.152), and was not influenced by bias, were consistently lower than
significantly influenced by the addition of the sphygmomanometric ones by some 10 mm Hg
ibuprofen (t-test: t= -1.20; df= 9; p= 0.300). systolic, and some 7 mm Hg diastolic, as
Introduction or withdrawal of piroxicam did not expected.
induce appreciable DPB changes within the The relative, percentual, changes in systolic
amlodipine subgroup (ANOVA: F3,15= 0.342; p= BP during this study are presented in Figure 2. A
0.796) nor in comparison to the control group sharp increase in phase I and III is clearly seen in
(ANOVA: F2,28= 1.736; p=0.195). the lisinopril/hydrochlorothiazide subgroups
Longitudinal comparison of DBP changes in taking ibuprofen or piroxicam, while in the
the four intervention subgroups showed amlodipine subgroups or in phase II
significant fluctuations (ANOVA: F2,80= 4.018; p= (acetaminophen), the baseline values did not vary
0.022; 2 = 0.091), much more pronounced in the substantially.
lisinopril/hydrochlorothiazide group (ANOVA:

e377 Can J Clin Pharmacol Vol 15 (3) Fall 2008:e372-e382; October 24, 2008
©2008 Canadian Society for Pharmacology and Therapeutics. All rights reserved.
Interaction between antihypertensives and NSAIDs in primary care: a controlled trial

TABLE 4 Automatically recorded sitting systolic blood pressure changes during the study periods

Period Control Control Intervention Intervention Intervention Intervention

L/H AM L/H±IB L/H±PX AM±IB AM±PX
Phase 0 138.921.1 138.1±10.1 139.3±16.1 133.316.5 144.817.4 130.210.4
(baseline)
Phase I 134.319.0 137.4±15.1 144.417.1* 149.421.1** 140.5±21.1 130.616.4
Phase II 129.615.7 135.3±11.6 133.920.8 132.918.4 142.020.4 131.415.6
Phase III 134.018.1 134.4±13.0 139.515.1 142.421.2* 137.621.4 125.48.6
Means standard deviations of the data
*p = 0.021 – 0.040; **p = 0.001 – 0.02
Acronyms: AM= amlodipine; IB= ibuprofen; L/H= lisinopril/hydrochlorothiazide; PX= piroxicam.

FIG. 2 Percentual changes from baseline values in mean standing systolic blood pressure
during the study periods

115 L/H.IB
110
L/H.PX
AM.IB
105 AM.PX
100

95

90
0 I II III phase

AM.IB= amlodipine±ibuprofen; AM.PX= amlodipine±piroxicam;

L/H.IB= lisinopril/hydrochlorothiazide±ibuprofen; L/H.PX= lisinopril/hydrochlorothiazide±piroxicam.
Error bars represent CI .95 of the calculated % differences.

Good blood pressure control (i.e. <140/90 observed between-group differences were
2
mm Hg in the sitting position) was obtained in 68 insignificant (χ =0.130; df 2; p= 0.937). The blood
of the 88 examinees (77.3%) at the inception of pressure control did not change appreciably
2
this trial. This high success rate was evenly during the formal study in the control (χ = 0.269;
distributed across the study arms, amounting at df 3; p= 0.966) nor in the amlodipine
2
76.9% among the control subjects, at 79.3% in the interventional arm (χ =0.251, df 3; p= 0.961),
lisinopril/hydrochlorothiazide intervention while in the lisinopril/hydrochlorothiazide arm it
subgroup (subsequently receiving either ibuprofen was markedly impaired by the addition of
2
or piroxicam; n= 29), and at 75% in the ibuprofen or piroxicam (χ =10.188; df 3; p=0.017;
amlodipine intervention subgroup (n= 20); the phases I and III in Table 5).

Can J Clin Pharmacol Vol 15 (3) Fall 2008:e372-e382; October 24, 2008 e378
©2008 Canadian Society for Pharmacology and Therapeutics. All rights reserved.
Interaction between antihypertensives and NSAIDs in primary care: a controlled trial

TABLE 5 Blood pressure control during the trial

Control group L/H+NSAIDS group AM+NSAIDS group

Period (n= 39) (n= 29) (n= 20)
NT* HT** NT HT NT HT
Phase 0 76.9% 23.1% 79.3% 20.7% 75.0% 25.0%
(baseline)
Phase I 74.4% 25.6% 44.8% 55.2% 70.0% 30.0%
Phase II 71.8% 28.2% 75.9% 24.1% 70.0% 30.0%
Phase III 74.4% 25.6% 51.7% 48.3% 75.0% 25.0%
*NT= normotensive, i.e. BP <140/90 mm Hg; **HT= hypertensive, i.e. BP ≥140/90 mm Hg in the seated position
Acronyms: AM= amlodipine; L/H= lisinopril/hydrochlorothiazide

Body weight, contrary to the expectations, did not research. First, it was not double blind but open
change significantly during this study (ANOVA: with the prescriber physician unaware of the
F2,77=1.813; p=0.159). In the control group all the results, and the assessor physician unaware of the
changes were within 0.3% limits (p >0.870), while prescribed drugs (“one and a half blind”). It was
in the intervention subgroups the average increase also not placebo controlled (hardly acceptable on
during the assumption of ibuprofen or piroxicam ethical grounds because of osteoarthritis severity).
was 0.4 kg (0.45%; p=0.230), and the maximal Second, we have not studied the global
increase was observed in phase I with piroxicam cardiovascular risk of these interactions (e.g.
[from 79.6±13.4 (CI.95=74.12-85.08) to 81.4±14.0 procoagulant or proinflammatory peculiarities)
(CI.95=75.68-87.12) kg; an average increase by but just the impact on arterial pressure.
2.2%; p=0.122]. Side effects in this study were Comparison with some recent studies or reviews
25-28
minor and expected; e.g., three patients in the may therefore be ill advised. Third, due to the
amlodipine study group and five in the amlodipine number of suitable patients willing to participate
control group complained of some ankle edema (122 out of possible 223 or 54.7%; enrolled 88 or
but none withdrew from the trial. 39.5%), the relatively small sample size limits the
power to prove possibly relevant differences
DISCUSSION between ibuprofen and piroxicam concerning
blood pressure control (just a trend was shown
The present study was not sponsored, so we could indicating piroxicam as a more potent interactant),
only afford to give the drugs refunded by the and a selection bias might impair the
Croatian Institute for Health Insurance. Over 95% extrapolability of the results. However, in clinical
of the prescriptions to the Croatian population are terms, the distinction between piroxicam and
currently covered with this insurance, provided ibuprofen in this sense is probably tenuous and
the prescribed drugs are on the “positive list”30 insignificant.
(i.e., coxibs and some other NSAIDs were not Of course, this study has several advantages
enlisted). Among the available drugs, we chose as well. It was performed in a busy family
the ones that are most prescribed, ibuprofen, practice, highly resembling the real life
acetaminophen and piroxicam. The design of the circumstances in a transitional, post communist
study was atypical since placebo could not be country. The factorial design with crossing-over
included because all the examinees had to take of NSAID regimens enabled us to better delineate
pain medications for severe osteoarthritic the role of individual agents. Since some authors
symptoms, and the control group (comparable describe acetaminophen as much less prone to the
hypertensives with no degenerative hip or knee studied interaction4,13,29, which others deny3,28, we
disease) was included just to offer an insight into have included this drug as an “indifferent”,
possible confounders, such as climatic or diet placebo-like agent during the wash-out interval
alterations. There are several limitations of this between two “hard” NSAID periods.
study, which also point to directions for future Acetaminophen distinctly ameliorated hypertension

e379 Can J Clin Pharmacol Vol 15 (3) Fall 2008:e372-e382; October 24, 2008
©2008 Canadian Society for Pharmacology and Therapeutics. All rights reserved.
Interaction between antihypertensives and NSAIDs in primary care: a controlled trial

control in this trial, showing remarkably little effect reported significant weight gain implicating
on blood pressure. However, only a placebo- volume expansion. Radack et al. 4 did not observe
controlled study could discern none from its weight gain with ibuprofen nor with
slight, residual prohypertensive potential. In this acetaminophen, while Klassen et al.8 reported a
respect, the distinction of acetaminophen from significant increase in body weight among 100
other COX inhibitors may be due to its peculiar hypertensives treated with naproxen. These
mechanism of action.31 discrepancies deserve further study and
We have confirmed the prohypertensive clarification.
activity of ibuprofen and piroxicam, known for
decades.2-29 On the other hand, the observed SUGGESTIONS
increase in blood pressure was much higher in our
hypertensive examinees (some 8-12/6-8 mm Hg) 1. For most hypertensive patients with
than in general populations20,21 (some 3-4/1-2 mm osteoarthritis or other conditions requiring chronic
Hg). This outstanding worsening of preexistent pain relief, particularly if at increased risk of
hypertension is clinically relevant, especially for hypertensive and/or atherosclerotic complications
elderly patients with polymorbidity, exposed to (e.g. elderly, diabetics, with impaired renal
additional cardiovascular risk factors (e.g. function), acetaminophen appears to be the safest
diabetes, nephropathy). treatment, while ibuprofen, piroxicam and some
Blood pressure control during this study was others (such as meloxicam and most coxibs)
remarkably good, achieving normotension in over should be avoided. 3-19,23- 29
75% of the examinees. The only exception was 2. The NSAIDs’ prohypertensive effect, due
registered in the lisinopril/hydrochlorothiazide more to vasoconstriction than to fluid retention, is
subgroups while receiving ibuprofen or piroxicam, much stronger in hypertensive than in
when the therapeutic efficacy/effectiveness was normotensive subjects. It is seemingly dose
almost halved! NSAID-induced increase in blood dependent (as shown in other trials3,7,10,12,19) and
pressure is presumably dose-related, as shown slightly fading over time.
with aspirin: low doses of 100 mg/day did not 3. Almost all antihypertensive drugs lose some
interfere with the control of hypertension10,12,19 , of their efficacy when combined with NSAIDs.
while doses of 300 mg/day did.11,19 Moreover, we Calcium channel blockers are an exception,
have observed a downward trend in this adverse becoming drugs of choice for the subset of
effect over time (phase I vs. phase III), which hypertensive population needing concomitant
deserves further investigation since in a long run analgesic/anti-inflammatory treatment.
the interaction may become clinically less
important. Acknowledgements
Our data indicate that the fixed-dose The authors are grateful to Žarko Bajić of
lisinopril/hydrochlorothiazide combination, and Biometrika Healthcare Research, Zagreb, Croatia
by inference most diuretics and ACE inhibitors, for skilful statistical help in planning this trial and
lose a lot of their antihypertensive effect through in data evaluation.
an interaction with some NSAIDs, which is
concordant with the majority of published trials3-
12,14,16,17,19
but not all.13 On the other hand, REFERENCES
amlodipine, and by inference most calcium channel 1. Pavličević I, Rumboldt Z, Rumboldt M.
blockers, be they dihydropyridines 5,8,17,23,24 or Untoward interactions between antihypertensives
and nonsteroidal anti-inflammatory drugs [in
nondihydropyridines9, resist this untoward
Croatian, summary in English]. Liječ Vjesn
interaction and are best suited for hypertensive 2005;127:168-72.
patients taking concomitant NSAIDs. 2. Antman EM, DeMets D, Loscalzo J.
Finally, since we have not observed a Cyclooxygenase inhibition and cardiovascular
significant increase in body weight during the risk. Circulation 2005;112:759-70.
intake of the NSAIDs, it seems that the observed 3. Chalmers JP, West MJ, Wing LM, Bune AJ,
BP elevation was largely due to vasoconstriction Graham JR. Effects of indomethacin, sulindac,
and less so to volume expansion. Others8-10,16 have naproxen, aspirin, and acetaminophen in treated

Can J Clin Pharmacol Vol 15 (3) Fall 2008:e372-e382; October 24, 2008 e380
©2008 Canadian Society for Pharmacology and Therapeutics. All rights reserved.
Interaction between antihypertensives and NSAIDs in primary care: a controlled trial

hypertensive patients. Clin Exp Hypertens 15. Morgan TO, Anderson A, Bertram D. Effect of
1984;A6:1077-93. indomethacin on blood pressure in elderly
4. Radack KL, Deck CC, Bloomfield SS. people with essential hypertension well
Ibuprofen interferes with the efficacy of controlled on amlodipine or enalapril. Am J
antihypertensive drugs. A randomized, double- Hypertens 2000;13:1161-7.
blind, placebo-controlled trial of ibuprofen 16. Savenkov MP, Ivanov SN, Broskaya SA.
compared with acetaminophen. Ann Intern Med Antihypertensive effect of enalapril and
1987;107:628-35. lisinopril administered in combination with
5. Morgan T, Anderson A. Interaction of nonsteroidal anti-inflammatory agents [in
indomethacin with felodipine and enalapril. J Russian]. Ter Arkh 2001;73:27-31.
Hypertens 1993;11 (suppl 5):S334-8. 17. Morgan T, Anderson A, MacInnis RJ. ACE
6. Perneger TV, Whelton PK, Klag MJ. Risk of inhibitors, beta-blocking drugs, calcium channel
kidney failure associated with the use of blocking drugs and diuretics for the control of
acetaminophen, aspirin, and nonsteroidal elevated blood pressure in the elderly: a double
antiinflammatory drugs. N Engl J Med blind crossover study in previously untreated
1994;331:1675-9. patients. Am J Hypertens 2001;14: 241-7.
7. Gurwitz JH, Avorn J, Bohn RL, Glynn RJ, 18. Fogari R, Zoppi A, Carretta R. Effect of
Monane M, Mogun H. Initiation of indomethacin on the antihypertensive efficacy of
antihypertensive treatment during nonsteroidal valsartan and lisinopril: a multicentre study. J
anti-inflammatory drug therapy. JAMA Hypertens 2002;20:1007-14.
1994;272:781-6. 19. Dabrowski R, Kowalik I, Maciag A, Sosnowski
8. Klassen DH, Jane LH, Young DY, Peterson CA. C, Szwed H. Aspirin 300 mg significantly
Assessment of blood pressure during naproxen attenuates hypotensive effects of ACE-inhibitor
therapy in hypertensive patients treated with in single-blind, cross-over, randomized
nicardipine. Am J Hypertens 1995; 8:146-53. comparison to aspirin 100 mg dose in
9. Houston MC, Weir J, Gray J, et al. The effects hypertensive patients with metabolic syndrome.
of nonsteroidal anti-inflammatory drugs on ESC Congress Munich 2004. Eur Heart J
blood pressure of patients with hypertension 2004;25 (Abstract Suppl):663; #3806.
controlled by verapamil. Arch Intern Med 20. Pope JE, Anderson JJ, Felson DT. A meta-
1995;155:1049-54. analysis of the effects of nonsteroidal anti-
10. Polonia J, Bonaventura I, Gama G, et al. inflammatory drugs on blood pressure. Arch
Influence of non-steroidal anti-inflammatory Intern Med 1993;153:477-84.
drugs on renal function and 24h ambulatory 21. Johnson AG, Nguyen TV, Day RO. Do
blood pressure-reducing effects of enalapril and nonsteroidal anti-inflammatory drugs affect
nifedipine gastrointestinal therapeutic system in blood pressure? A meta-analysis. Ann Intern
hypertensive patients. J Hypertens 1995;13:925- Med 1994;121:289-300.
31. 22. Aw TJ, Haas SJ, Liew D, Krum H. Meta-
11. Gurwitz JH, Everitt DE, Monane M, et al. The analysis of cyclooxygenase-2 inhibitors and
impact of ibuprofen on the efficacy of their effects ob blood pressure. Arch Intern Med
antihypertensive treatment with 2005;165:490-6.
hydrochlorothiazide in elderly persons. J 23. Armstrong EP, Malone DC. The impact of
Gerontol A Biol Sci Med Sci 1996;51 M74-9. nosteroidal anti-inflammatory drugs on blood
12. Guazzi MD, Campodonico J, Celeste F, et al. pressure, with an emphasis on newer agents.
Antihypertensive efficacy of angiotensin Clin Ther 2003;25:1-18.
converting enzyme inhibition and aspirin 24. Morgan T, Anderson A. The effect of
counteraction. Clin Pharmacol Ther 1998;63:79- nonsteroidal anti-inflammatory drugs on blood
86. pressure in patients treated with different
13. Thakur V, Cook ME, Wallin JD. antihypertensive drugs. J Clin Hypertens
Antihypertensive effect of the combination of (Greenwich) 2003;5:53-7.
fosinopril and HCTZ is resistant to interference 25. White WB. Hypertension associated with
by nonsteroidal anti-inflammatory drugs. Am J therapies to treat arthritis and pain. Hypertension
Hypertens 1999;12:925-8. 2004;44:123-4.
14. Conlin PR, Moore TJ, Swartz SL, et al. Effect of 26. Borer JS, Simon LS. Cardiovascular and
indomethacin on blood pressure lowering by gastrointestinal effects of COX-2 inhibitors and
captopril and losartan in hypertensive patients. NSAIDs: achieving a balance. Arthritis Res
Hypertension 2000;36:461-5. Ther 2005;7 (suppl 4):S14-S22.

e381 Can J Clin Pharmacol Vol 15 (3) Fall 2008:e372-e382; October 24, 2008
©2008 Canadian Society for Pharmacology and Therapeutics. All rights reserved.
 Interaction between antihypertensives and NSAIDs in primary care: a controlled trial

27. Whelton A. Clinical implications of nonopioid

analgesia for relief of mild-to-moderate pain in
patients with or at risk for cardiovascular
disease. Am J Cardiol 2006;97:3-9.
28. Wilson SL, Poulter NR. The effect of non-
steroidal anti-inflammatory drugs and other
commonly used non-narcotic analgesics on
blood pressure levels in adults. J Hypertens
2006;24:1457-69.
29. Johnson J, Weinryb J. Safe pharmacologic
treatment strategies for osteoarthritis pain in
African Americans with hypertension, and renal
and cardiac disease. J Natl Med Assoc
2006;98:1126-35.
30. Dragun A, Russo A, Rumboldt M.
Socioeconomic stress and drug consumption:
unemployment as an adverse health factor in
Croatia. Croat Med J 2006;47:685-92.
31. Aronoff DM, Oates JA, Boutaud O. New
insights into the mechanism of action of
acetaminophen: its clinical pharmacologic
characteristics reflect its inhibition of the two
prostaglandin H2 synthases. Clin Pharmacol
Ther 2006;79:9-19.

Can J Clin Pharmacol Vol 15 (3) Fall 2008:e372-e382; October 24, 2008 e382
©2008 Canadian Society for Pharmacology and Therapeutics. All rights reserved.

View publication stats