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Bangladesh Journal of Medical Science Vol. 15 No. 03 July’16

Original article
Cost Analysis of Combination Diuretic Therapy with Ace-Inhibitors to Diuretic Therapy without 

Ace-Inhibitors in Heart Failure Patients
Pribadi FW1 , Dwiprahasto I2, Thobari JA2

Abstract:
Background: Heart failure is the final stage of the entire heart disease and become a major 
health problem because of the high morbidity and mortality. Diuretic combination therapy 
with ACE inhibitors compared to diuretic therapy without ACE inhibitors will affect the costs 
and hospitalization for heart failure patients; so it can be used to study Pharmacoeconomics. 
Method and Design: This study is an analytic observational retrospective cohort study design. 
Researchers compared the cost analysis between groups having diuretic combination therapy 
with an ACE inhibitor and diuretic therapy without ACE inhibitors. Data taken with a total 
sampling of heart failure databases claimed prescribing health insurance between January 1, 
2010 until December 31, 2011. Results: Out of the 377 patients of the study population, 64 
patients received combination therapy with ACE inhibitors and diuretics, and 60 patients 
received diuretic therapy without ACE inhibitors. The analysis showed that the total cost was 
Rp. 4.96 million and Rp. 5.14 million; the average total inpatient days a year was 10.67 days and 
7.00 days. Conclusion: This study showed that the diuretic combination therapy with an ACE 
inhibitor is more cost-effective. Further research is needed to assess the total costs and 
effectiveness of therapy with more number of subjects and longer periods.
Key Words: diuretics; ACE-inhibitors; heart failure; cost analysis

Corresponds to:  Fajar Wahyu Pribadi, Department of Pharmacology, The Faculty of Medicine, Jenderal 
Soedirman University, Indonesia. E-mail:	tarique@iium.edu.my	|	m.tariqur.rahman@gmail.com.

1. Fajar Wahyu Pribadi, Department of Pharmacology, The Faculty of Medicine, Jenderal Soedirman
University.

2. Iwan Dwiprahasto,

3. Jarir At Thobari,
Department of Pharmacology and Toxicology, The Faculty of Medicine, Gadjah Mada University

Introduction:
Heart failure is the final stage of the entire heart 
disease and to this day remains a major health 
problem because of the high morbidity and 
mortality1. Figures prevalence, incidence or new 
cases a year which is the highest frequency cause of 
hospitalization in patients aged 65 years or more. 
Figures hospital discharge increased2.3. Unfavorable 
prognosis with survival rates of 50% and 10% in a 
period of 5 and 10 years and also occupy about 30-
35% of the total hospitalisation4. In addition, Case 
fatality rates after hospitalization within 30 days 
was 10.4%; whereas in 1 year was 22% and in 5 
years was 42.3%5.
In Indonesia, there was 13.396 hospitalized 
cases, outpatient 16,431 cases with a case fatality 
rate 13.42%6. Lodging in Central Java Province 

categorized in groups of heart and blood vessel 
disease or cardiovascular diseases such as heart 
disease, stroke, hypertension is the number of 833 
094 cases (54.33%) with a prevalence of 0.14%, 
which means there are 10,000 people 14 people 
who suffer from heart failure6,7.
Costs incurred for the management of heart failure 
was 5.9% of the total health budget in Amerika8. 
While the National Heart, Lung, and Blood Institute 
estimates that the total cost of heart failure in 2010 
of 39.2 million dollars to the direct cost of 35.1 
million dollar9. In developing countries, consume 
between 1-2% of the total health budget and two-
thirds is the cost of hospitalization10.
Given standard therapy for severe heart failure 
is a loop diuretic, an ACE inhibitor, digoxin, 
β-blocker or a combination thereof. In two RCTs 

Bangladesh Journal of Medical Science Vol. 15 No. 03 July’16. Page : 368-375



369

Cost	Analysis	of Combination	Diuretic	Therapy

(CONSENSUS and SOLVD-Treatment) conducted 
in 2,800 patients with a diagnosis of mild to severe 
heart failure who were given enalapril and placebo 
showed the results of therapy with ACE inhibitors 
reduce the risk of death (RRR = Relative Risk 
Reduction) by 27% in CONSENSUS and 16 % in 
SOLVD-Treatment. In addition to the SOLVD-
Treatment also showed RRR of 26% in hospital 
admission for worsening heart failure. This 
advantage arises when combined with conventional 
therapy11.

In a meta-analysis of diuretic therapy showed a 
decrease in mortality of 75% (OR = 0:25, 95% CI 
0.84% to 0:07%; p = 0:03; ARR 8.2%; NNT = 
12) and an increase in exercise capacity 63% (OR
= 0:37, 95% CI 0.1% to 0.64%) 12. Incremental
cost-effectiveness to ACE inhibitors in the AIRE
and HOPE shows an estimate of $ 2.800 / YOLS
(Year of Life Saved) and $ 15,000 / YOLS, while
the estimated lifetime treatment for $ 5,000 /
YOLS and 8.500 / YOLS. Research on RALES get
that diuretics decrease heart failure hospitalization

Figure 1. The selection process of the study

Sum (%) 

Total 
Characteristics 

Diuretic & ACE Diuretik tanpa 
p-value

N=124 Inhibitor ACE Inhibitor 
(n=64) n (%) (n=60) n (%) 

Sex 
- Female 48 (38,7) 28 (43,8) 30 (33,2) 0,234 
- Male 76 (61,3) 36 (56,2) 40 (46,8) 

Age 
- < 45 year 4 (3,2) 2 (3,1) 2 (66,1) 0,668 
- 45-64  year 63 (50,8) 35 (54,7) 28 (46,7) 
- > 64  year 57 (46,0) 27 (42,2) 30 (50,0) 

Room Class
- I 75 (60,5) 40 (62,5) 35 (58,3) 0,092 
- II 45 (36,3) 20 (31,3) 25 (71,7) 
- ICU 4 (3,2) 4 (6,3) 0 (0) 

Comorbid 
- No 97 (78,2) 51 (79,7) 46 (76,7) 0,684 
- Yes 27 (21,8) 13 (20,3) 14 (23,3) 

Table 1: Characteristics of Subjects Research

Source: processed secondary Data 2012



370

Pribadi	FW	,	Dwiprahasto	I,	Thobari	JA

of 250 (663 versus 413, placebo versus diuretic)13. 
Then research the total cost of torasemide and 
furosemide was 1,502 DEM and DEM 1.863. 
While the cost effectiveness (annual cost per patient 
with improved NYHA class) is 3.954 DEM and 
DEM 7.60514 . All of these studies was to compare 
between each drug with placebo. While the study 
was to compare between diuretic Spannheimer. 
Therefore, this study sought to obtain information 
on cost analysis diuretic combination therapy with 

ACE inhibitors to diuretic therapy without ACE 
inhibitors in heart failure patients Askes participants 
so that the results of this study will be used as a 
basis for the study of other Pharmacoeconomics.
Research methods:
This study was an observational study with 
retrospective cohort study design study using a 
database of participants claimed prescribing health 
insurance from PT. Askes Persero. The data 
used is the patient data for one year, ie between 

No. Variabel Shapiro-Wilk 
Statistic df sig 

1 Hospitalization Cost 0,794 124 0,000 
2 Services and laboratories Cost 0,690 124 0,000 
3 Drug Costs 0,643 124 0,000 
4 Total Costs 0,850 124 0,000 
5 CER/Day 0,763 124 0,000 

Table 2. Normality Test

Source: processed secondary Data 2012

Mean 
(±SD) 

Long Hospitalization Diuretik & ACE Diuretik without ACE p 
Inhibitor Inhibitor 
(n=64) (n=60) 

Day/ Year 7,00 10,67 0,000 
(4,42) (4,34) 

Source: processed secondary Data 2012

Table 3. Long Hospitalization between diuretics and ACE inhibitor group with 
diuretics without ACE inhibitors

Rupiah, in Thousand (Mean ± SD) 

Cost 
Diuretic& Diuretic without 

p 
ACE Inhibitor ACE Inhibitor 

(n=64) (n=60) 
Hospitalization Cost 2782,81 3473,33 0,001 

(2620,41) (2262,51) 
Services and laboratories Cost 754,44 635,75 0,836 

(873,22) (661,10) 
Drug Costs 1572,13 859,95 0,000 

(1765,38) (1241,72) 

Total Costs 4960,72 5143,06 0,620 
(3677,66) (2920,60) 

Table 4. Bivariate Analysis Regarding the cost of diuretics and ACE inhibitor group with 
diuretics without ACE inhibitors

Source: processed secondary Data 2012



371

Cost	Analysis	of	Combination	Diuretic	Therapy

January 2010 until December 2011, which were 
then followed for 1 year. The perspective adopted 
in this study is the perspective of payers in this 
case is the PT. Askes Persero. Inclusion criteria 
for this study is the case group participants Askes 
patients with a diagnosis of heart failure and age 
over 18 years (has entered the adult criteria), a 
patient undergoing diuretic combination therapy 
with an ACE inhibitor and diuretic therapy without 
ACE inhibitors, have the data about the patient in 
the form of : patient data (Askes ID number, date 
of birth, and gender), data about the prescription 
(prescription date, trade name drugs, drug dosage, 
frequency of administration, the amount of drug 
administered and the cost of drugs), the data and 
the length of hospital diagnosis in hospital . The 
exclusion criteria in this study include the pregnant 
condition, there is a diagnosis of malignancy. The 
results of this study were analyzed using the data 

processing software and presented in tabular form 
and narrative.
Ethical approval was taken prior study.
Research result:
Subjects Characteristics
Based on the data claimed prescribing heart failure, 
there were 377 patients with heart failure. The 
subjects of the study after the selection is based 
on inclusion and exclusion criteria, were allocated 
into two groups, the first group of cases (n = 64) 
who received diuretic combination therapy with an 
ACE inhibitor. The second was the control group 
(n = 60) who received diuretic therapy without 
ACE inhibitors
The selection process of the study are shown on 
Figure 1
Characteristics of subjects in each group are 
shown in Table 1.
Based on results of the normality test using the 

CER Rupiah, in Thousand (Mean ± SD) 
n Day/ Year 

Therapy 
- Diuretic & ACE 64 824,77 
Inhibitor (487,61) 
- Diuretic without ACE 60 468,61 

Inhibitor (202,40) 
p value 0,000 

Age 
<45 year 4 886,30 

(445,79) 
- Diuretic & ACE 2 927,29 
Inhibitor (206,89) 

- Diuretic without 2 845,32 
ACE Inhibitor (739,37) 

45-64 year 63 636,03 
(387,17) 

- Diuretic & ACE 35 748,62 
Inhibitor (465,82) 

- Diuretic without 28 495,30 
ACE Inhibitor (184,38) 

> 64 year 57 654,15 
(447,63) 

- Diuretic & ACE 27 915,90 
Inhibitor (523,76) 

- Diuretic without 30 418,58 

Table 5. Bivariate Analysis CER between diuretics and ACE inhibitor group with 
diuretics without ACE inhibitors



372

Pribadi	FW	,	Dwiprahasto	I,	Thobari	JA

Shapiro-Wilk test the dependent variable in this 
study, namely the cost of hospitalization, cost of 
services and laboratories, drug costs, and the total 
cost, and CER / Day unknown that all the data 
were not normally distributed because all p values 
(sig) <0.05, so that the results of this study can 
not be generalized and can only be inferred for 
research subjects. Then the analysis followed by 
Mann-Whitney test, while for analysis seen from 
age followed by the Kruskal-Wallis test. Normality 
test results can be seen in Table 2 below:
Effectiveness Hospitalization
Based on Table 3 it can be seen that the time of 
hospitalization was there are different views on the 

number of days in heart failure patients who use 
drugs diuretics and ACE inhibitors with diuretics 
without ACE inhibitors (p = 0.000) in which 
the number of days of hospitalization mean that 
using diuretics and ACE inhibitors as much as 7 
days things this is less than the number of days of 
hospitalization average with diuretics without ACE 
inhibitors as many as 10.067 days.
This shows that the treatment of heart failure patients 
using diuretics and ACE inhibitor drugs turned out 
to have a higher CER compared to treatment with 
diuretics without ACE inhibitors, but the results of 
Table 3 indicate that the treatment of heart failure 
patients using diuretics and ACE inhibitor drugs 

ACE Inhibitor (140,62) 
p value 0,313 

Sex 
Female 48 724,14 

(510,27) 
- Diuretic & ACE 28 944,98 
Inhibitor (564,10) 

- Diuretic without 20 414,96 
ACE Inhibitor (139,30) 

Male 76 607 
(340,71) 

- Diuretic & ACE 36 731,28 
Inhibitor (403,21) 

- Diuretic without 40 495,43 
ACE Inhibitor (224,29) 

p value 0,307 

Comorbid 
Non Comorbid 97 672,74 

(458,15) 
- Diuretic & ACE 51 861,58 
Inhibitor (536,26) 

- Diuretic without 46 463,38 
ACE Inhibitor (207,50) 

Comorbid 27 579,49 
(197,59) 

- Diuretic & ACE 13 680,40 
Inhibitor (153,47) 

- Diuretic without 14 485,79 
ACE Inhibitor (190,95) 

p value 0,710 

Source: processed secondary Data 2012



373

Cost	Analysis	of	Combination	Diuretic	Therapy

turned out to be the number of days average for 
each hospitalization is smaller than treatment with 
diuretics without ACE inhibitors. Both of these 
results it can be concluded that the use of diuretics 
and ACE inhibitor drugs able to reduce the number 
of days of hospitalization in heart failure patient by 
1 day for each hospitalization.
Charge
Based on Table 4 it can be seen that the cost of 
hospitalization and medication costs incurred in 
the year between the heart failure patients using 
diuretics and ACE inhibitor drugs with diuretics 
without ACE inhibitors showed a difference (p = 
0.001) at the cost of hospitalization and (p = 0.000) 
at the cost of drugs. While the cost of services and 
laboratories (p = 0.836) and total cost (p = 0.620) 
were issued in the year between the heart failure 
patients using diuretics and ACE inhibitor drugs 
with diuretics without ACE inhibitors showed no 
difference (p>0.005)
Relationship Therapy, Hospitalization and Costs
Based on Table 5 it can be seen that the CER 
difference from the number of days of hospitalization 
for one year in patients with heart failure between 
the use of drugs diuretics and ACE inhibitors 
with diuretics without ACE inhibitors showed a 
significant difference (p = 0.000).
At CER analysis based on age, it can be seen that 
there is no difference CER seen from inpatient 
day for a year for each hospitalization in patients 
with heart failure between the ages <45 years, 45-
64 years , and more than 64 years, because all p 
values> 0.05.
On gender, based on table 5 it can be seen that there 
is no difference CER inpatient day for a year for 

each hospitalization in patients with heart failure 
between female and male, because p values> 0.05.
In comorbidities, it is known that there is no 
difference CER views of inpatient day for a year 
in patients with heart failure between the non-
comorbid and comorbid, because all p values> 
0.05.
Discussion:
The results showed that the subjects in this study 
mostly over the age of 45 years the majority of men 
(61.3%). These results have the same results with 
the NHANES study and the NHLBI who reported 
that the age 45 years and older have a higher 
prevalence of heart failure more than under the age 
of 45 Year9. In addition, the prevalence occurs in 
men more than women15.
For the results obtained that the hospitalization 
costs incurred for hospitalization diuretic group 
without ACE inhibitors during the year is greater 
than the costs incurred for hospitalization group 
diuretics and ACE inhibitors during the year. This 
happens because of the length of stay (in days) 
diuretic and ACE inhibitor groups fewer than 
longer hospitalization diuretic group without ACE 
inhibitors. These results have similarities with the 
results of research conducted by Tilson L et al. 
where the standard therapy group diuretic and 
lowers the cost of hospitalization.
However, in these studies there was a drop of only 
5%. This is probably caused by the studies conducted 
using specific diuretic that spironolactone16.
At the cost of services and laboratory results, it 
was found that the group of diuretics and ACE 
inhibitors to pay more than the diuretic group 
without ACE inhibitors, but was not statistically 

Mean 
(±SD) 

Cost Diuretik & Diuretik without �  
ACE Inhibitor ACE Inhibitor 

(n=64) (n=60) 
Total Cost* 4960,72 5143,06 182,34 

(3677,66) (2920,6) 
Outcome 
Day 7,00 10,67 3,67 

(4,42) (4,34) 
CER Incremental 
CER (Day)* 824,77 468,61 356,16 

(487,97) (202,40) 
*in thousand Rupiah

Tabel 6. Summary



374

Pribadi	FW	,	Dwiprahasto	I,	Thobari	JA

significant (p> 0.005). This occurs because the 
amount of the diuretic and ACE inhibitor group 
more than the amount of the diuretic group without 
ACE inhibitors. In addition, the group of diuretics 
and ACE inhibitors are a class rooms comparison 
in between class I (62.5%), class II (31.3%) and 
ICU (6.3%). While in the diuretic group without 
ACE inhibitors are a class room on the comparison 
between class I by 58.3%, amounting to 71.7% 
class II and ICU at 0%.
While the results of the cost of the drug, also 
found that subjects in the group of diuretics and 
ACE inhibitors to pay more than the diuretic 
group without ACE inhibitors, although it was not 
statistically significant (p> 0.005). This happens 
because there are additional costs ACE inhibitor 
drugs in the group of diuretics and ACE inhibitors.
On the total costs incurred, it was found that 
the two groups nearing cost almost the same 
(difference of only 182.34). Diuretics without ACE 
inhibitor group issued a total cost of greater but not 
statistically significant (p> 0.005). This happens 
because the total cost is the sum of the cost of 
hospitalization, cost of services and laboratory and 
drug costs. Although the cost of hospitalization in 
the diuretic group without ACE inhibitors greater, 
but the cost of services and laboratory and drug 
costs less than the group issued a diuretic and ACE 
inhibitors
In the CER results consisting of CER (days / year) 
is divided into several outcomes, namely between 
the diuretic and ACE inhibitors with diuretics 
without ACE inhibitors, the patient’s age, gender, 
co-morbidities. It was found that the CER (days / 
year) diuretic and ACE inhibitor group is greater 
than the diuretic group without ACE inhibitors. 
This happens because the average days diuretic and 
ACE inhibitor group is smaller than the diuretic 
group without ACE inhibitors.
Results of CER (days/ year) found that the largest 
is at age <45 years, and the smallest is at the age 
of 45-64 years. This happens because the average 
Number of patients smallest at age <45 years, and 
the largest is at the age of 45-64 years.
In the CER results obtained views of gender CER 
(days/ year) is greater in women than men. This 
happens because the average average days of 
women less than men even though statistically 
not significant (p> 0.005). While the results 
of co-morbidities seen CER (day) in the group 
without comorbidities greater than the group with 

comorbidities. This happens because the average 
days /year group without comorbidities smaller 
than the group with comorbidities.
Another result of this study is the combination 
therapy showed diuretic and ACE inhibitors lower 
the results of inpatient day average compared to 
diuretic therapy without ACE inhibitors.
In connection with the above results, similar studies 
have been done on the ATLAS study which found 
that ACE inhibitors decrease hospitalization for 
heart failure by 24% (P = 0.002). This research 
was carried out for 36 months in 3164 heart failure 
patients. While the PEP-CHF trial conducted in 850 
patients with heart failure found that ACE inhibitors 
decrease the rate of heart failure hospitalization 
for 1 year by 35% (RR = 0.65, 95% CI 0.98 to 
0:43)18.
Conclusion:
The total cost diuretic combination therapy with 
ACE inhibitors in patients with heart failure Askes 
participant in a year is Rp. 4.96072 million, -. The 
total cost diuretic therapy without ACE inhibitors 
in heart failure patients Askes participant in a year 
is Rp. 5.14306 million, -. Effectiveness diuretic 
combination therapy with ACE inhibitors in heart 
failure patients Askes participants judging from the 
total number of days hospitalized in a year is 7 
days. Effectiveness diuretic therapy without ACE 
inhibitors in heart failure patients Askes participants 
judging from the total number of days hospitalized 
in a year is 10.67 days. ICER therapy diuretic 
therapy without ACE inhibitors in heart failure 
patients seen in total number of days hospitalized 
in a year is Rp. 356 160, -
Research limitations:
This study has several limitations, especially in a 
short period of study and number of samples are 
minimal. Further research is needed to assess the 
total costs and Effectiveness of therapy with more 
number of subjects and a period of over one year.
Acknowledgments:
The author would like to acknowledge the support 
of the head of PT. Askes Persero Branch of Kudus, 
Director of Mardi Rahayu Hospital, Chairman 
of the Program of Basic Medical Sciences and 
Biomedical Program, Chair of Pharmacology and 
Toxicology Faculty of Medicine, Gadjah Mada 
University and Dean of the Faculty of Medicine and 
Health Sciences University of General Sudirman 
Purwokerto.
Conflict of interest: None



375

Cost	Analysis	of	Combination	Diuretic	Therapy

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