Treatment optimization of angiotensin converting enzyme inhibitors and associated factors in Ayder Comprehensive Specialized Hospital: a cross-sectional study
Atey et al. BMC Res Notes
Treatment optimization of angiotensin converting enzyme inhibitors and associated factors in Ayder Comprehensive Specialized Hospital: a cross-sectional study
Tesfay Mehari Atey 0
Tsegay Teklay 2
Solomon Weldegebreal Asgedom 0
Haftay Berhane Mezgebe 0
Gebrehiwot Teklay 0
Molla Kahssay 1
0 Department of Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Mekelle University , Mekelle, Tigray , Ethiopia
1 School of Public Health, College of Health Sciences, Semera University , Semera, Afar , Ethiopia
2 School of Pharmacy, College of Health Sciences, Mekelle University , Mekelle, Tigray , Ethiopia
Background: Angiotensin-converting enzyme inhibitors have morbidity and mortality benefits in heart failure. Failure to optimize treatment using these medications increases hospitalizations, worsens signs and symptoms of heart failure, and reduces the overall treatment outcome. Therefore, the main purpose of this study was to assess the practice of treatment optimization of these medications and associated factors. Results: A hospital-based cross-sectional study was conducted on 61 ambulatory heart failure patients, recruited using a convenience sampling technique, from February 25 to May 24, 2016 at the cardiology clinic of Ayder Comprehensive Specialized Hospital. Descriptive, inferential and Kaplan-Meier 'tolerability' analyses were employed. All patients were taking only enalapril as part of their angiotensin converting enzyme inhibitor treatment. According to the 2013 American College of Cardiology/American Heart Association guideline, about fourth-fifth (80.3%) of the patients were tolerating to the hypotensive effect of enalapril. The dose of enalapril was timely titrated (every 2-4 weeks) and was optimized for only 11.5 and 27.8% of the patients, respectively. Considering the tolerance, timely titration, and dose optimization, only 3.3% of the overall enalapril treatment was optimized. Multivariate regression results showed that the odds of having timely titration of enalapril for patients who were taking enalapril and calcium channel blockers were almost 20 times [adjusted odds ratio (AOR) = 21.68, 95% confidence interval (CI) 1.23-383.16, p < 0.036] more compared to patients who were taking enalapril and β-blockers. A Log Rank Chi Square result showed a 19.42 magnitude of better toleration of enalapril (p < 0.001) for patients who were taking enalapril for more than 1 year compared to less than a year. Conclusion: This study provides a platform for assessment of the treatment optimization practice of enalapril, which remains the pressing priority and found to be poor in the ambulatory setting, despite a better tolerability to the hypotensive effect of enalapril. We call for greater momentum of efforts by health care providers in optimizing the treatment practice to benchmark with other optimization practices.
Treatment optimization; Angiotensin converting enzyme inhibitors; Heart failure
Heart failure (HF) is a complex clinical syndrome that
results from any structural or functional impairment of
ventricular filling or ejection of blood [
]. It is one of the
major and progressive causes of morbidity and
mortality in most developed and some developing countries.
Current therapeutic strategies have been designed to
counter the progression of heart failure and to improve
‘meaningful’ survival by using medications that inhibit
the remodeling process [
]. One of these strategies is to
use angiotensin-converting enzyme inhibitors (ACEI) in
HF patients, which is considered nowadays as one of the
important and necessary steps towards an effective
management of patients with HF [
The available evidence suggests that in chronic HF, high
doses of ACEI are more effective than low ones. The
current recommended clinical approach is to target ACEI
dosing regimens to be similar to those used in the
clinical trials, which demonstrated mortality and morbidity
benefits. When titrated appropriately, ACEI are
generally well tolerated and target doses can be achieved and
maintained in the majority of patients with HF [
Clinical practice guidelines, published by both the
Agency for Health Care Policy and Research, and the
American College of Cardiology Foundation/American
Heart Association (ACCF/AHA), reflect the findings of
these studies. According to these guidelines, every effort
should be made to increase the dose of ACE inhibitors to
the target doses shown in clinical trials to decrease
mortality and morbidity with close monitoring when
managing chronic HF [
]. Moreover, studies such as the
prospective evaluation by Messner Pellenc found that a
daily dose of 20 mg of enalapril could be reached in a high
proportion of patients with HF at good tolerability and
improved outcomes . The target doses used in clinical
trials were 10 mg ramipril per day, 20–40 mg enalapril
per day, 150 mg captopril per day, 10–35 mg lisinopril
per day or 4 mg trandolapril per day [
]. Concerning the
algorithm for HF management, we followed the same
algorithm as outlined in ACCF/AHA and World Health
Organization (WHO) guidelines [
Regarding tolerability of ACEI, renal function, serum
potassium, and signs and symptoms of a cough and
angioedema should be assessed within 1–2 weeks of
initiation of therapy and periodically thereafter [
1, 5, 8,
]. Most of HF patients (85–90%) can tolerate ACEI
. However, a study done in Sweden reported that 77%
of the patients experienced angioedema within the first
3 weeks after starting treatment [
A number of prospective observational studies have
reported that patients with HF discharged from
hospital and maintained on ‘high’ ACEI doses had improved
clinical outcomes compared to those receiving low-dose
therapy. The benefits include improved patients’
symptom status, low rates of death and re-hospitalization,
thus incurring lower costs [
]. Lack of ACEI
treatment optimization significantly affects these beneficial
treatment outcomes for patients with HF [
the practice of treatment optimization for this
important class of medications is not assessed so far in Ayder
Comprehensive Specialized Hospital (ACSH). This study
was conducted in identifying the gaps in the
implementation of optimal dosing of ACEI in the treatment of adult
ambulatory HF patients in ACSH.
A hospital-based cross-sectional study was employed
at the cardiac unit of ACSH, Northern Ethiopia from
February 25 to May 24, 2016. This institution is a
public hospital that gives inpatient and outpatient services
for millions of population in Tigray region and nearby
regions. Heart failure patients with severe illness are
usually admitted and treated as inpatients while stable
patients receive care chronically as ambulatory or
outpatients. The source population was all adult ambulatory
HF patients who were taking HF medications. The study
population in this study was all adult ambulatory HF
patients who were obtaining services at the cardiology
unit of ACSH and whose treatment regimen was ACEI.
Approximately 256 ambulatory HF patients who were
taking ACEI regularly visit the cardiac clinic.
Considering 1.96 for the standard normal variable with a 5% level
of significance, 80% power of the study, 95% confidence
interval (CI), 5% margin of error and 10% contingency,
the sample size was calculated to be 61. A convenient
sampling technique was employed to select the samples
from the study population.
Ambulatory HF patients who were taking ACEI as part
of their treatment for at least 3 months, whose baseline
information was clearly depicted in their medical records,
who had a regular follow-up at the clinic and who were
18 years old and above were included in the study. On
the other hand, ambulatory HF patients who were using
ACEI for < 3 months, with no baseline data and younger
than 18 years of old were excluded from the study. The
overall patient selection process is summarized in Fig. 1.
Data were collected retrospectively by three trained
data collectors (2 nurses and 1 pharmacist) through
reviewing the patients’ medical records for a period
of 3 months. The structured data abstraction tool was
developed according to the 2013 ACCF/AHA and WHO
guidelines recommendations [
]. The data
abstraction tool was pre-tested in 10% of the sample size (i.e., 6
medical records). Completeness of the collected data was
supervised and monitored adequately by the
investigators during the data collection process.
Heart failure patients attending the ambulatory cardiac clinic [n=898]
Heart failure patients not taking ACEI [n=642]
Ambulatory heart failure patients on ACEI with a regular follow-up [n=256]
Ambulatory heart failure patients excluded from the study ( 3 months follow-up period, no baseline data, < 18 years age) [n=195] Ambulatory heart failure patients included in the study [n=61]
Data analysis was carried out using Statistical Package
for Social Sciences (SPSS® Statistics) program version
21 (SPSS; Chicago, IL, USA). Descriptive statistics such
as frequency, percentage, mean, and standard deviation
(SD) were employed to summarize patient, clinical, and
Logistic regression analysis was performed to relate
independent variables to treatment optimization of
ACEI. From the univariate analysis, those variables with
p < 0.2 and clinically important factors were selected for
multivariate binary logistic regression analysis. The
multivariate binary logistic regression analysis was also used
to assess the predictability of the independent variables
for treatment optimization of ACEI and to estimate the
odds ratios (OR), 95% confidence intervals (CI) and p
values. A ‘tolerability’ analysis for ACEI was carried out
using the Kaplan–Meier analytic method. A Log Rank
(Mantel–Cox), Breslow (Generalized Wilcoxon) and
Tarone–Ware tests were employed in the overall
comparisons of the ‘tolerability’ curves. The association was
declared significant for the aforementioned analyses at
p < 0.05.
ACEI was deemed to be ‘tolerated’ if the blood pressure
was greater than 80/60 mmHg, serum creatinine was less
than 3 mg/dL, serum potassium was < 5.5 mEq/L and no
history or current complaint of a cough or angioedema.
Otherwise, the ACEI was deemed to be ‘non-tolerated’.
Angioedema was defined as swelling of lips, mouth,
tongue, or airway in patients receiving ACEI therapy,
where no other clinical cause was identified and where
there were no recurrent symptoms following cessation of
the drug [
The time interval between the dose titration was said to
be ‘appropriate’ if the tolerated dose was timely titrated
(every 2–4-week interval). Time for a dose titration was
considered as ‘inappropriate’ if the dose was not titrated
within 2–4 weeks of the time interval. A dose of ACEI
was said to be ‘optimized’ when once the drug is initiated
and has been titrated up by 12.5 mg three times daily
for captopril, 10 mg two times daily for lisinopril, and
2.5–5 mg daily for enalapril to the higher doses according
to 2013 ACCF/AHA guideline. Lastly, the overall ACEI
treatment was deemed to be ‘optimized’ when the dose of
ACEI was optimized with timely titration, and the patient
tolerated the ACEI [
The socio-demographics and clinical characteristics
of the study participants are summarized in Table 1.
According to the medical records of the study patients,
more than half (57.4%) of the patients were males and
were dwelling in urban areas (68.9%). Besides this, about
one-third (34.4%) of the patients were in the age group of
53–69 years (mean 51.77 years; SD ± 17.56 years; range
19–83 years). Forty-five percent of the study patients
had evidence of hypertension as a co-morbid disease
followed by diabetes mellitus (34.4%). With reference to the
cause of HF, 57.4% of the documented cause of HF were
rheumatic valvular heart disease, followed by
hypertension (28%). Furthermore, 42.6% of the patients had HF
with reduced ejection fraction. For the majority (n = 28,
62.2%) of the study participants, the ejection fraction was
50%. The evidence for classifying the ejection fraction
was based on the hospital’s reference value (60 ± 10%).
In view of that, patients with ejection fraction ≤ 40%
were categorized as HF with reduced ejection fraction
The mean duration of diagnosis of HF for the patients
was 1.8 years (SD ± 1.3 years; range 3 months to 6 years).
According to the ACCF/AHA staging system, above
fourth-fifth (83.6%) of the patients had stage “C” HF
(Fig. 2). In addition to staging, the most prevalent
category of NYHA class was class IV, accounted for 39.3%,
followed by class III (31.1%) (Fig. 3). All of the study
participants were using only enalapril as part of their ACEI
treatment. The mean duration of taking this medication
was 1.5 years (SD ± 1.2 years; range 3 months to 6 years;
95% CI 1.2–1.8) (Fig. 4).
All of the study patients were using one or more other
types of HF medications in addition to enalapril. The
combination of the ACEI and diuretics accounted for
about half (49.2%) of the prescribed medications followed
by a combination of the ACEI and β-blockers (34.4%)
Treatment optimization and associated factors
Regarding the toleration using blood pressure as a
monitoring parameter, about fourth-fifth (80.3%) of the study
subjects were tolerating to this effect during the periods
of apparent titration periods but few patients were not
tolerating their medication during the third titration
period. On the contrary, for the majority (88.5%) of the
study subjects, their dose was not timely titrated and
near three-fourth (72.1%) of the patients’ dose was not
optimized during these titration periods. The majority of
the patients had a timely titration of ACEI during fourth
and beyond titration periods. Doses of ACEI were not
optimized during the third titration period, compared to
the fourth and beyond titration periods. Considering the
above three factors (tolerance, timely titration, and dose)
in combination, the ACEI treatment was not optimized
for almost all (96.7%) of the patients (Table 2 and Fig. 6).
Proportion of ACCF/AHA staging system
Proportion of NYHA classification system
The results of univariate and multivariate logistic
regression analysis showed that no factor was
significantly associated with the toleration, dose optimization
and overall treatment optimization of ACEI at p < 0.05.
Moreover, the following factors that interact with heart
failure were assessed for their association with tolerability
of ACEI. These were: (1) cardiac events: coronary heart
disease, atrial fibrillation, uncontrolled hypertension, and
arrhythmia; (2) non-cardiac events: pulmonary
infections, pulmonary emboli, diabetes mellitus, worsening
renal function, hyperthyroidism, anemia, and pregnancy;
and (3) drugs: negative inotropic medication
(azithromycin, β-blockers, non-dihydropyridine calcium channel
blockers, and itraconazole), direct cardiotoxics
(anticancers, ethanol, and amphetamine) and drugs with sodium
and water retaining properties (non-steroidal
antiinflammatory drugs, COX-2 inhibitors, glucocorticoids,
and sodium-containing drugs). These factors were not
found to have any statistically significant association, at
the crude level, with the ACEI toleration.
On the other hand, the results of regression analysis for
factors associated with timely titration are summarized
in Table 3 after controlling the independent variables
and incorporating those variables with p value less than
0.2 (including duration of diagnosis and types of other
concomitant medications) into the multivariate logistic
regression analysis. From the multivariate analysis, the
odds of having timely titration of ACEI for patients who
were taking ACEI and calcium channel blockers were
almost twenty times (AOR = 21.68, 95% CI 1.23–383.16,
p = 0.036) more compared to patients who were taking
ACEI and β-blockers (Table 3).
Kaplan–Meier ‘tolerability’ analyses
The event of interest during the Kaplan–Meier (KM)
‘tolerability’ analysis method in this study was ACEI
treatment toleration and the units of measurement
along the x-axis were the duration of taking ACEI in
months. Patients who were taking ACEI for more than
1 year were tolerating their medication in a better way
than patients who were taking ACEI for less than a
year. The test of equality of survival distributions for
the duration of ACEI treatment showed the Chi Square
results of 19.42, 21.78 and 21.47 for the Log Rank
(Mantel–Cox) (p < 0.001), Breslow (Generalized Wilcoxon)
(p < 0.001) and Tarone–Ware (p < 0.001) respectively
Any other combinations*
ACEI and calcium channel blockers
A comparison of KM survival curves for the types of
HF medications revealed that none of the combinations
of HF medications provide any effect on the toleration
of the medications by the study participants. The test of
equality of survival distributions for the different types of
heart failure medications showed the Chi Square results
of 1.204, 0.878 and 0.933 for the Log Rank (Mantel–Cox)
(p = 0.752), Breslow (Generalized Wilcoxon) (p = 0.831)
and Tarone–Ware (p = 0.817) respectively (Fig. 8).
The study assessed treatment optimization practice of
ACEI among ambulatory HF patients at the cardiac clinic
of ACSH. According to 2013 ACCF/AHA
recommendation, the majority (80.3%) of the study patients were
tolerating the ACEI provided blood pressure as a
monitoring parameter. The probable explanation for this
finding might be supported by the evidence that most of the
patients were maintained on low doses for a long period
of time. Moreover, there might be poor patients’
awareness on reporting the potential side effects associated
with ACEI. This finding (80.3% tolerance to ACEI) was
congruent with studies done in the USA that reported
tolerance rate of 80% [
] and Australia that reported
75% rate [
]. This similarity could be related to the
maintenance of patients on a similar dose without
uptitration for a long duration of the period. Another
possible explanation could also be the similarity of black
patients and the matched white patients in
socio-demographic and clinical characteristics [
Concerning timely titration of ACEI, the majority of
patients’ medication was not timely titrated (that is, every
ACEI and beta-blockers
ACEI and diuretics
0 10 20 30 40 50 60
Fig. 5 Medications profile among ambulatory heart failure patients at the cardiac clinic of Ayder Comprehensive Specialized Hospital, 2016. *ACEI
and statins, ACEI and anticoagulants, ACEI and digoxin. ACEI, angiotensin converting enzyme inhibitor
ACEI, angiotensin converting enzyme inhibitor
a The cut off point for “yes” was 5 and for “no” was 0–4, considering the five titration periods from first up to the current
2–4 weeks) as per the recommendations. The absence of
concordance on the selection of appropriate appointment
date between the patients and physicians could be the
possible explanation for this finding. Likewise, the
medications for patients with longer duration of diagnosis was
not timely titrated as substantiated by the finding that
patients whose HF diagnosed for the duration of fewer
than 1.6 years had 19.4% of timely titration compared to
0% timely titration for patients with 3.26 and above years’
duration. This might be associated with the resistance of
AOR, Adjusted odds ratio; CCB, calcium channel blockers; CI, Confidence interval; COR, Crude odds ratio
* Statistically significant at p < 0.1
** Statistically significant at p < 0.05
a Any other combinations: ACEI and statins, ACEI and anticoagulants, ACEI and digoxin
physicians on consideration of the essentiality of upward
titration of ACEI and might be due to the high ratio of
patients per healthcare professional which could hinder
the quality of medical as well as pharmaceutical care
secondary to the absence of clinical pharmacy specialist
at the cardiology clinic.
Besides the above findings, the doses of ACEI were
not optimized for the majority of the study participants
(72.9%). The patients in this study were taking a low dose
of ACEI for longer periods of time without proper
titration. This poor dose optimization practice corresponded
with a study done in England that reported 75% [
probable reason for this finding might be attributed to
the poor quality of health care due to less team-work and
lower involvement of clinical pharmacists in the hospital
setting and the absence of updated hospital guidelines.
Moreover, the reason why patients’ doses were not
optimized were allied to fear of adverse effects and the
physicians claimed that patients becoming intolerant to
higher doses. Despite the differences in the definition
of ‘optimal’ doses of ACEI in different clinical settings,
a number of surveys suggest that clinicians often prefer
the use of low doses of ACEI, and the perception that low
doses are as effective as high ones are quite prevalent. In
addition, clinicians rarely titrate ACEI dose according to
blood pressure [
The overall treatment in the present finding was not
optimized because the dose was not optimized and
timely titrated in most of the patients, and some of the
patients were not tolerating the medications. This leads
to the overall poor treatment optimization practice
in the hospital despite the obvious favorable effects of
ACEI therapy using a cascaded higher dose. Tailoring
therapy to achieve a desired neurohormonal response
and improve therapeutic outcomes have been
]. Unless optimally titrated, exacerbation of
heart failure occurs commonly in these patients and
contribute to the compromised quality of life for these
]. There are multitudes of reasons given for
why patients were either not on ACEI or at low doses
of them objecting the optimum titration. In summary,
the potential obstacles may be attributable to fear of
adverse effects [
], patients’ inconvenience to
appointment dates selected; high patient load with small
number of physicians; absence of physicians’ team-work or
less team-work spirit with clinical pharmacists and other
health care providers; less access and awareness to the
up-to-date guidelines by the clinicians; and physicians’
low knowledge, attitude and practice towards ACEI
The multivariate binary logistic regression analysis
showed that the combination of medications was only
found to be significantly associated with timely
titration. Accordingly, patients who were taking ACEI and
calcium channel blockers were more likely to have timely
titration compared to patients who were taking ACEI
and β-blockers. This might be related to side effects of
calcium channel blockers, which are common and
easily identifiable by the patients. Therefore, the patients
preferred to report these side effects and likely to have
a short duration of appointment than patients who were
taking β-blockers. On the other hand, most of the
sociodemographics and clinical characteristics of the study
participants were not found to be significantly
associated with timely titration, dose optimization, and overall
The Kaplan–Meier (KM) ‘tolerability’ analysis method
showed that patients who were taking ACEI for more
than 1 year were tolerating their medication in a better
way than patients who were taking ACEI for less than a
year. The majority of the side effects of ACEI is seen in
the early phases of treatment and then wanes with the
progression of time.
There was a certain limitation in this study. The
crosssectional nature of this study did not allow follow-up of
the study participants, which could have provided a
better design for identifying the factors associated with the
This study provides a platform for assessment of the
treatment optimization practice of ACEI (enalapril),
which remains the pressing priority and found to be poor
in the ambulatory setting, despite a better tolerability to
the hypotensive effect of enalapril. The combination of
enalapril and calcium channel blockers is found to
contribute positively to timely titration. Accordingly, we call
for greater momentum of efforts by health care
providers in optimizing the treatment practice to benchmark
with other optimization practices in order to improve the
heart failure management.
ACCF/AHA: American College of Cardiology Foundation/American Heart
Association; ACEI: angiotensin converting enzyme inhibitors; ACSH: Ayder
Comprehensive Specialized Hospital; AOR: adjusted odds ratio; CCB: calcium channel
blockers; CI: confidence interval; COR: crude odds ratio; HF: heart failure; NYHA:
New York Heart Association; WHO: World Health Organization.
TMA and TT involved in the conception and design of the study, developed
data collection tools, supervised data collection, analyzed data and wrote
the manuscript. SW, MK, HBM, and GT involved in writing and editing of the
manuscript. All authors read and approved the final manuscript.
The authors are indebted to all participants of the study.
The authors declare that they have no competing interests.
Availability of data and materials
The datasets supporting the conclusions of the study are included in the
article. Any additional data will be available on request.
Consent to publish
Ethics approval and consent to participate
The study was approved by the Institutional Review Board of Collage of Health
Sciences, Mekelle University. A letter of support was obtained from the
medical director’s office of the hospital. All results of this research were based on
the use of secondary data and the data collection was performed
retrospectively. Therefore, obtaining informed written consent form from the study
participants was not applicable in this study but the study was conducted
in accordance with the ethical standards of the institutional and national
research committee. The study also adhered to the declarations of Helsinki.
The study was not supported by any funding agent.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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