Research Article

Adverse drug reaction monitoring with angiotensin converting

enzyme inhibitors: A prospective, randomized, open-label,
comparative study
Nishant V. Sangole, Vaishali N. Dadkar

ABSTRaCT
Objectives: Angiotensin converting enzyme inhibitors (ACEIs) are known to possess
different chemical structures, and change in structure of a drug can bring about change in
its adverse drug reaction (ADR) profile. The study aims to observe the incidence and severity
of ADRs between the di-carboxyl group containing ACEIs (d-ACEIs) versus phosphonate
Department of Pharmacology, group containing ACEIs (p-ACEIs), in patients suffering from essential hypertension.
Pad. Dr. D.Y. Patil Medical College, Materials and Methods: One hundred and twenty patients with essential hypertension
Hospital and Research Center, were randomized into four groups receiving enalapril, lisinopril, ramipril, and fosinopril.
Nerul, Navi Mumbai, India They were followed up for four months, to observe the clinical efficacy along with the
associated ADRs.
Received: 28-01-2009
Results: Mild, dry brassy cough (% incidence; 95% CI) was observed with d-ACEIs (6.6%;
Revised: 11-06-2009
Accepted: 03-02-2010 0 to 15.6) versus p-ACEI (20%; 5.7 to 34.3), in which the cough observed was moderate-
to-severe in intensity and two patients required treatment discontinuation (P < 0.05). No
DOI: 10.4103/0253-7613.62408 cases of hypotension were observed with the use of d-ACEIs, whereas, two patients on
p-ACEI (6.6%; 0 to15.6) had hypotension (P < 0.05). Three patients (10%; 0 to 20.7) on
d-ACEIs had nausea, which was not observed with p-ACEI treatment (0%) (P < 0.05).
Correspondence to: Conclusions: The phosphonate group in p-ACEIs may have a probable relationship with
Dr. Nishant V. Sangole increase in the incidence and severity of ADRs such as dry brassy cough and hypotension.
E-mail: dr_nishants@yahoo.com The di-carboxyl group in d-ACEIs may have a probable relationship with increase in the
incidence of ADRs like nausea.

Keywords: Angiotensin converting enzyme inhibitor, adverse drug reaction, angiotensin

converting enzyme inhibitors, antihypertensive, enalapril, fosinopril, lisinopril, ramipril,
dicarboxyl, phosphonate

Introduction we should have maximum data on their pattern of utilization

and the adverse drug reactions.
Angiotensin converting enzyme inhibitors (ACEIs) have The purpose of the present study was to observe the
a well-established role in the management of essential incidence and severity of adverse drug reactions between
hypertension. They are structurally classified as sulfhydryl the di-carboxyl group containing ACE inhibitors (namely
containing ACEIs, for example, captopril, fentiapril, zofenopril, enalapril, lisinopril, and ramipril) versus the phosphonate
and so on; di-carboxyl containing ACEIs namely enalapril, group containing ACE inhibitors (namely fosinopril), in patients
lisinopril, perindopril, quinapril, moexipril, and so on; and suffering from essential hypertension.
phosphonate containing ACEIs namely fosinopril, on the
basis of their binding with the angiotensin converting enzyme Materials and Methods
(ACE).[1] It is a well-known fact, that the activity of a drug can One hundred and twenty newly diagnosed patients (83 male,
be modified by changes in the structure of the drug. Hence, it 37 female) suffering from stage I / II essential hypertension,
can be hypothesized that they may have different patterns of according to JNC-VII guidelines, [2] without any underlying
adverse drug reactions (ADRs). This study was prompted by comorbid conditions or complications, aged between 20 and
the fact that a large number of people suffer from essential 70 years, were enrolled in the study after obtaining informed
hypertension and ACEIs certainly are among the most widely consent and due approval of the ethics committee. It was a
prescribed agents in its treatment. It is therefore imperative that prospective, parallel, open-label, randomized, comparative

Indian J Pharmacol | Feb 2010 | Vol 42 | Issue 1 | 27-31 27

 Sangole and Dadkar: ADR monitoring with ACE inhibitors

trial, and the patients were divided into four groups of 30 dropped out, of which four subjects were withdrawn due to lack
each. Each group received enalapril (2.5 mg), lisinopril (2.5 of three consecutive follow-up visits and one subject dropped
mg), ramipril (2.5 mg), and fosinopril (10 mg), respectively, out, as the subject could not bear the expenses involved. New
once daily, in the morning with breakfast. As it was an open- cases were enrolled to compensate the dropouts.
label study, to avoid selection bias, a randomization chart was The observed age distribution of subjects receiving ACEIs
prepared beforehand using the Random Allocation Software in each study group is expressed in Figure 2. It is evident that
(version 1.0.0; developed by M.Saghaei and Isfahan). In this a majority (48.3%) of the subjects were in the age range of
randomization chart, the subject numbers were allocated from 46 – 55 years, whereas, only 7.5% of the population was in the
1 – 160 (anticipating study dropouts) in four groups. Each subject age group of 26 – 35 years.
was enrolled on a first-come basis and received treatment as The various adverse drug reactions observed in the
per his / her randomization number. The investigational drugs study subjects were dizziness, cough, hypotension, diarrhea,
were prescribed to the study subjects and purchased from hyperkalemia, neutropenia, musculoskeletal pain, fatigue,
the hospital pharmacy. The individual dose was subsequently headache, nausea, and skin rash [Table 1].
titrated in case of inadequate blood pressure control, which As evident from the findings [Table 1], significant differences
was predefined for blood pressure levels of < 140 / 90 mmHg. with regard to the incidence and severity were observed only
On confirming the diagnosis, the baseline blood pressure with cough, hypotension, and nausea.
in the left arm (sitting position) was recorded after allowing 10
Cough
minutes of rest for each subject. The blood pressure of all the
Two subjects (%incidence; 95%CI) on enalapril (6.6%; 0
subjects was monitored on an hourly basis, for four hours on
to15.6), two subjects on lisinopril (6.6%; 0 to 15.6), two subjects
day 1, after the first dose was administered, under supervision.
on ramipril (6.6%; 0 to 15.6), and six subjects on fosinopril
Every subject was followed up for four months, which included
eight follow-ups at an interval of 15 days. During every follow- (20%; 5.7 to 34.3) had dry cough. A total of 12 cases (nine males
up, the blood pressure in the left arm (sitting position) was and three females) of cough were observed [Table 1]. All the
recorded after allowing 10 minutes of rest, the compliance with subjects gave a history of dry, non-productive cough. Details
therapy and use of concomitant medicines was documented; any regarding the intensity of the cough and other related features
additional anti-hypertensive medication precluded the subject are tabulated in Table 2.
from continuing in the study. Hematological and biochemical Subjects receiving enalapril, lisinopril, and ramipril (the
examinations were performed at baseline and end of the study. d-ACEIs) developed dry cough after one to one-and-a-half
Adverse Events (AEs) if any, were documented during the follow- months of therapy. In all these subjects, the cough was
up visit and their causality was assessed using the World Health mild in nature and there were no specific aggravating or
Organization–Uppsala Monitoring Center (WHO-UMC) causality relieving factors. The cough continued throughout the period
assessment criteria.[3] For grading adverse drug reactions, such of observation in all the subjects and did not cause any
as, dizziness, cough, musculoskeletal pain, fatigue, headache,
and nausea, a visual rating scale (VRS) was employed; cough Figure 1: Gender distribution of patients receiving ACEI for hypertension
was further evaluated on the basis of its interference in routine
activities and sleep disturbances in the subject. To propose a
hypothesis, after comparing the incidence of ADRs between
the two groups, namely di-carboxyl containing ACE Inhibitors
and phosphonate containing ACE Inhibitors, we employed the
statistical hypothesis test of difference in proportion (Z-test),
to calculate the P-value in terms of significance.
Results
The unicentric, prospective, randomized, comparative,
open-label study included 120 patients suffering from stage I / II
essential hypertension. These included 83 males and 37 females
randomized in each study group [Figure 1]. It was evident that Figure 2: Age distribution of study subjects receiving ACEI for
the number of males in each study group was more than the hypertension
females. Their mean (± S.D.) age was 50.7 (± 16.9) years;
70
baseline blood pressure (systolic / diastolic), 157.4 (±15.2) /
No. of patients (n=120)

58
60
101.4 (±9.1) mm Hg; and body mass index, 24.0 (±2.5) kg/m2.
50
The target blood pressure of < 140/ 90 mm Hg was achieved
40 31
in all subjects by appropriate individualized dose titration. The
30 22
mean (±SD) blood pressure at end of the study was observed
20
as 129.6 (±10.2) / 89.4 (±7.1) mm Hg. The study drugs were 9
tolerated by the majority, except in five subjects, who presented 10 0 0

with adverse events such as neutropenia (n = 1), severe dry 0

20-25 26-35 36-45 46-55 56-65 66-70
cough (n = 2), and skin rash (n = 2), which warranted treatment
Age group (years)
discontinuation. During the course of the study five subjects

28 Indian J Pharmacol | Feb 2010 | Vol 42 | Issue 1 | 27-31

 Sangole and Dadkar: ADR monitoring with ACE inhibitors

disturbances in their routine activities or any kind of sleep cough within fiftten days of initiating therapy in four subjects
disturbances. It did not warrant discontinuation of therapy. and within twenty days of initiating therapy in two subjects.
On the other hand, six subjects (five males and one female) The cough worsened at night, in the lying down position, in all
receiving fosinopril (belonging to p-ACEI) presented with dry the six subjects. It was progressive from mild-to-moderate in
four subjects, but did not interfere in their routine activities.
Table 1: Two subjects were discontinued from fosinopril and started on
Summary of incidence of all adverse drug reactions observed in
another anti-hypertensive agent. The cough subsided on the
the study subjects (n = 120) seventh day after discontinuation of fosinopril.
The overall incidence of cough appeared to be higher in
Observed Enalapril Lisinopril Ramipril Fosinopril males compared to females. This could be attributed to the
adverse drug n = 30 n = 30 n = 30 n = 30
reactions total total total total fact that the number of males enrolled in this study was higher.
number number number number Hypotension
(%) (%) (%) (%)
There were no cases of hypotension observed with enalapril
Dizziness 2 (6.6%) 4 (13.3%) 1 (3.3%) 4 (13.3%) (0%), lisinopril (0%) or ramipril (0%). Although, two subjects
Cough* 2 (6.6%)* 2 (6.6%)* 2 (6.6%)* 6 (20%)* (%incidence; 95%C.I.) on fosinopril (6.6%; 0 to 15.6) had
Hypotension* 0* 0* 0* 2 (6.6%)* hypotension; one among them gave a history of associated
dizziness [Table 3].
Diarrhea 0 2 (6.6%) 0 1 (3.3%)
Nausea
Hyperkalemia 0 3 (10%) 2 (6.6%) 0
Three subjects (%incidence; 95%C.I.) on enalapril (10%; 0
Neutropenia 1 (3.3%) 0 0 0 to 20.7), three subjects on lisinopril (10%; 0 to 20.7), and three
Musculoskeletal 1 (3.3%) 1 (3.3%) 0 2 (6.6%) subjects on ramipril (10%; 0 to 20.7), all belonging to d-ACEIs,
pain presented with nausea. The nausea was mild-to-moderate in
Fatigue 1 (3.3%) 2 (6.6%) 0 2 (6.6%) intensity. The time of onset was 40 – 80 minutes after consuming
Headache 2 (6.6%) 0 1 (3.3%) 0 the drug and it lasted for another two to three hours in all
Nausea* 3 (10%)* 3 (10%)* 3 (10%)* 0* the subjects. There were no associated episodes of vomiting.
Nausea did not warrant discontinuation of therapy. On the other
Skin Rash 1 (3.3%) 1 (3.3%) 0 0
hand, not a single case of nausea was reported with fosinopril
* Indicates P < 0.05, Dicarboxyl group containing ACEIs, Phosphonate group
containing ACEI
(0%). A summary of these features is presented in Table 4.
Among the various adverse events reported in this study,
Table 2:

Cough seen in study subjects receiving the ACEIs for hypertension (n = 12).

Drug No. of cases Sex distribution Onset Nature Discontinuation Sleep

(M-Male and from therapy disturbances
F- Female)
Enalapril 2 1M+1F 1 month mild No No
Lisinopril 2 1M+1F 1 ½ months mild No No
Ramipril 2 2M+0F 1 – 1 ½ months mild No No
Fosinopril 6 5M+1F 15 – 20 days moderate-to-severe 2 subjects Yes
Dicarboxyl group containing ACEIs, Phosphonate group containing ACEI, Comparing the two groups, P < 0.05 using one tailed P-value.

Table 3: Table 4:

Hypotension seen in study subjects receiving ACEI for Nausea observed in study subjects receiving ACEI for
hypertension (n = 2). hypertension (n = 9)

Drug Mean B.P. Mean B.P. Dose range Cases of Drug No. of cases Intensity Time of onset Duration
(baseline) (After 1 month hypotension (minutes)
mmHg of therapy)
Enalapril 3 mild 40 – 45 2–3
mmHg
Enalapril 142/98 128/88 2.5 – 5 mg 0 Lisinopril 3 mild-to- 60 – 80 2–3
moderate
Lisinopril 140/100 126/88 2.5 – 5 mg 0 Ramipril 3 mild-to- 45 – 60 2–3
Ramipril 146/94 128/86 2.5 – 5 mg 0 moderate

Fosinopril 144/100 118/82 10 – 20 mg 2 Fosinopril 0 - - -

Dicarboxyl group containing ACEIs, Phosphonate group containing ACEI
Dicarboxyl group containing ACEIs, Phosphonate group containing ACEI
Comparing the two groups, P < 0.05 using one tailed P-value.
Comparing the two groups, P < 0.05 using one tailed P-value.

Indian J Pharmacol | Feb 2010 | Vol 42 | Issue 1 | 27-31 29

 Sangole, et al.: ADR monitoring with ACE inhibitors

every AE remained independent of one another and there was of starting therapy with fosinopril. On the other hand, none
no overlapping observed; except in one subject, who presented of the subjects in the other study group receiving enalapril,
with hypotension and dizziness. lisinopril, and ramipril had hypotension. As our sample size
was relatively small, further studies are required to confirm
Discussion
whether the incidence of hypotension is higher with fosinopril
Besides essential hypertension, ACEIs are increasingly used (p-ACEIs) and negligible with enalapril, lisinopril, and ramipril
for the management of several other conditions, such as, acute (d-ACEIs). This could also probably mean that the doses were
myocardial infarction, left ventricular systolic dysfunction, well titrated against the response in terms of the beneficial
chronic renal failure, and so on. Large multi-centric trials[4,5] effect on blood pressure.
have proved that ACEIs not only increase the life expectancy, Nausea with use of ACEIs is around 1–5% as reported in
but also improve the quality of life in high-risk patients suffering the literature.[7,9,13,15] It is somewhat higher with lisinopril as
from cardiovascular events. It appears that by their specific compared to enalapril and ramipril[7,13,15] and considerably
effect on myocardial and vascular cell growth, also referred to low with fosinopril.[9] Our findings indicated that the incidence
as remodeling, they have a greater protective potential than of nausea was higher (10%) with all three agents, namely,
any other class of anti-hypertensive drugs. enalapril, lisinopril, and ramipril (d-ACEIs), whereas, none
Ever since captopril (sulfhydryl group containing ACEI) was receiving fosinopril (p-ACEI) had nausea. From the point of
introduced as an anti-hypertensive agent in the year 1981, view of patient compliance, p-ACEI fosinopril appears to be
by the USFDA, many adverse effects with its use have been a better option, if patients complain of nausea with d-ACEIs.
reported. Several other ACEIs followed captopril over the years This kind of an increased incidence and severity of nausea with
to come and today we have a surfeit of ACEIs to choose from di-carboxyl containing ACE Inhibitors, may at some point be
with more or less a similar ADR profile. noted by clinicians with caution (although not serious), while
Our study was designed to monitor the various ADRs prescribing them. In such situations a phosphonate containing
seen with the ACEIs containing the di-carboxyl group (namely ACE Inhibitor may prove a suitable option. The causality needs
enalapril, lisinopril, and ramipril) and the phosphonate group to be confirmed by evaluating a larger number of subjects to
(namely fosinopril), with the aim to observe the incidence and make the study representative of the Indian population.
severity of ADRs between the two groups.
Based on the observations, it can be concluded that three
Among the 11 ADRs [Table 1] that were encountered with
ADRs, namely, cough, hypotension, and nausea seem to have
various ACEIs, only three ADRs namely cough, hypotension, and
a probable relationship with the functional group (di-carboxyl /
nausea elicited a significant difference related to their chemical
phosphonate). Cough and hypotension have a higher incidence
structure. The incidence of these ADRs was not related to the
and severity with p-ACEIs, whereas, nausea is associated only
age group of the study subjects.
with d-ACEIs.
Dry, brassy cough is commonly reported with the use of ACEIs
and is estimated to be in the range of 5–10%.[6-9] The cough is Limitations of this study
usually persistent, paroxysmal, non-productive, worsening in the Financial and time constraints not only restricted the
lying down position, and at times accompanied by a change in number of subjects recruited in our study, but also the duration
voice.[10] Studies have suggested the involvement of mediators of the follow-up period and the number of follow-up visits. As
such as, bradykinin, prostaglandins or substance P as mediators this study was limited to 120 subjects, incorporating more
of the cough.[11,12] A literature survey suggests about a 6% number of subjects in each group and conducting the study in
incidence of cough with enalapril, lisinopril, and ramipril,[6-8] different centers across India can establish a more accurate
whereas, it is reported to be higher (10%) with fosinopril.[9] causal relationship. There is a need for an increased number
In our study, the incidence of cough with enalapril, lisinopril, of follow-up visits, over a longer duration, to make this study
and ramipril was similar to that reported in literature, but broad-based and representative of the Indian population.
was distinctly higher (20%) in subjects receiving fosinopril. Scope for further work
It was interesting to note that some of the subjects (three Comparative studies which focus on the association of ADRs
males and one female) on fosinopril also complained of sleep with a change in the structure of ACE Inhibitors; involving all the
disturbances on account of cough, of which two (one male and three zinc-binding groups of ACE Inhibitors, namely, sulfhydryl,
one female) required discontinuation of drug as cough was di-carboxyl, and phosphonate are needed. A phosphonate
very troublesome. This could have possible repercussions on group replacing the di-carboxyl group was introduced with the
the long-term use of p-ACEIs. Hence, d-ACEIs could clinically intention to increase the potency of ACE Inhibitors. Further
be a better option over p-ACEIs since they are better tolerated studies can be carried out by introducing a newer zinc-binding
by hypertensive patients in the long term. However, this needs group in the ACE Inhibitors which may help in discovering a
further assessment in a larger sample of patients. prototype or an ideal ACE Inhibitor having a favourable ADR
The incidence of hypotension with the use of ACEIs is profile and good tolerability.
reported to be in the range of 2–5% and there is no significant
difference in the incidence of hypotension caused by d-ACEIs Acknowledgments
or by p-ACEIs.[7,9,13,14] However, in our study, hypotension The authors are indebted to the following doctors for their technical
was observed only in a few subjects receiving fosinopril support in this study: Hanumanthugari R, Patil D., Melmane P., Bansode
that needed reduction in dosage from 10 mg/day to 5 mg/ S.G., Yadav H., and Sawarkar S. We extend our special gratitude to
day. This feature was observed approximately after a month Dhume V.G. for his valuable contributions to this study.

30 Indian J Pharmacol | Feb 2010 | Vol 42 | Issue 1 | 27-31

 Sangole, et al.: ADR monitoring with ACE inhibitors

References 8. Williams B, Gosse P, Lowe L. The prospective, randomized investigation of safety

and efficacy of telmisartan versus Ramipril using ambulatory blood pressure
1. Ondetti MA, Rubin B, Cushman DW. Design of specific inhibitors of Angiotensin monitoring (PRISMA I). J Hypertens 2006;24:193-200.
converting enzyme: A new class of orally active hypertensive agents. Science
9. Bristol-Myers Squibb. Fosinopril prescribing information. Princeton (NJ). 1996.
1977;196:441-6.
10. Anonymous. Cough caused by Angiotensin converting enzyme inhibitors. Drug
2. U.S Department of Health and Human Services. The Seventh Report of Joint
Ther Bull 1994;32:28 and 55-56.
National Committee on prevention, detection, evaluation and treatment of high
blood pressure. August 28-29, 2004. 11. Ferner RE, Simpson JM, Rawlins MD. Effects of intradermal bradykinin after
3. Uppsala monitoring centre. The use of the WHO-UMC system for standardized inhibition of angiotensin converting enzyme. BMJ 1987;294:1119-20.
case causality assessment. Available from: http://www.who-umc.org/ 12. Morice AH, Lowry R, Brown MJ, Higenbottam T. Angiotensin converting enzyme
graphics/4409.pdf. [accessed on 2007 Nov 4]. and cough reflex. Lancet 1987;2:1116-8.
4. Heart Outcomes Prevention Study Investigators (HOPE). Effect of ACE 13. Cooper WD, Sheldon D, Brown D, Kimber GR, Isitt VL, Currie WJ. Post marketing
Inhibitor Ramipril on cardiovascular events in high risk patients. N Engl J Med surveillance of Enalapril. 1987;37:346-9.
2000;342:143-5. 14. Chu CS, Cheng KH, Lee KT, Lin TH, Lee ST, Su HM, et al. Tolerability of Ramipril
5. European Trial on Reduction of Cardiac events with Perindopril in stable Coronary 10 mg daily in high risk cardiovascular patients in Taiwan. Kaohsiung J Med Sci
Artery Disease (EUROPA) Investigators. Lancet 2003;362:782-8. 2005;21:511-6.
6. Arnolt MA, Damonte de Elia AR. Enalapril and cough. J Hypertension 1991;4:28A. 15. Schreiner M, Berendes B, Verho M, Langley A, Cairns V. Anithypertensive efficacy,
7. Moyses C, Higgins TJ. Safety of long-term use of Lisinopril for congestive heart tolerance and safety of long term treatment with Ramipril. J Cardiovasc Pharmacol
failure. Am J Cardiol 1992;70:91C-7C. 1991;18:S137-40.

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