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INTRODUCTION
Diabetic Nephropathy (DN) is a significant consequence resulting from diabetes and a major contributor to end-stage renal failure. The patient with diabetic nephropathy exhibits persistent albuminuria, lower limb edemas, hypertension, and increasing renal failure, as documented by Umanath et al., 2018. These symptoms significantly impact the patient's quality of life. Therefore, it is crucial to address this problem with appropriate treatment choices. Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Blockers (ARBs) are commonly used to treat diabetic nephropathy (Figure 1) (Du et al., 2022).
Angiotensin-Converting Enzyme (ACE) inhibitors decrease mortality and cardiovascular events in patients with cardiovascular disease or high-risk diabetes and slow the progression of Chronic Kidney disease (CKD) in patients with proteinuria (Jessup et al., 2009; National Kidney Foundation, 2004). ACEIs do not block the vasoconstrictor response to angiotensin II fully. According to that Blocking of the renin-angiotensin pathway with Angiotensin Converting Enzyme Inhibitors (ACE) concomitantly with Angiotensin Receptor Blockers (ARBs) has some physiological bases. Also, some increase in angiotensin II levels may occur in long term treatment with ACEIs leading to decrees in treatment efficacy of inducing vasoconstriction (Farquharson and Struthers, 2002). Two indications have been cited for the use of ACEIs and ARBs concomitantly: CKD with proteinuria and heart failure (Kuenzli et al., 2010). Many randomized controlled trials on patients with heart failure compared the combination therapy with ACE-inhibitor monotherapy showed that the combination therapy decreases cardiovascular morbidity. In contrast, ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) that was done on patients diagnosed with diabetes with end-organ damage or vascular disease, indicated that death and cardiovascular events did not decrease when using combination therapy with ACEIs and ARBs. It was associated with higher rates of adverse events, including Acute Kidney Failure (AKF) requiring dialysis and hyperkalemia. Moreover, there were 208 acute kidney failure events in 2690 patients on ACEi + ARB versus 170 in 4264 patients with ACEi or ARB monotherapy Also, 304 hyperkalemia events in 2818 patients on ACEi + ARB versus 208 in 4396 patients with ACEi or ARB monotherapy. Combination therapy in patients with proteinuria, although it has no definitive evidence that it is effective in improving clinically meaningful outcomes, it is suggested to be beneficial based on a meta-analysis of small trials (Kunz et al., 2008).
Antihypertensive medication use for hypertension patients not only lowers BP but also reduces the risk of CVD, cerebrovascular events, and death. Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin II Receptor Blockers (ARBs) are both first-choice groups of medications for treating high blood pressure, Calcium channel blockers and Thiazide diuretics are other treatment options. According to the American Heart Association, patients can start hypertension treatment with only one single agent, but for patients with persistent elevated blood pressure, the option of giving two drugs of different classes should be considered. Based on the recommendations, drug combinations that have similar mechanisms of action or clinical effects should be avoided due to less effectiveness and potential harm when used together (e.g., ACE inhibitors, ARBs) (Whelton et al., 2018). In 2015, The Saudi Food and Drug Authority approved a letter issued to healthcare professionals to inform them about the avoidance of using medicines that act on the renin-angiotensin-aldosterone system concomitantly, such as ARBs, ACEI, or direct renin inhibitors. The safety concerns of combining ACEI and ARBs together are related to increased risk of hyperkalemia, worsening of kidney function and hypotension (Elfawal, 2015). The SFDA advised healthcare professionals that concomitant use of ARBs and ACEIs should be avoided unless medically justified. If their use was necessary, it should only be under supervision and with monitoring of renal function electrolytes and blood pressure. Data regarding the prevalence of ACEIs and ARBs concomitant use among the Saudi population are limited therefore, the purpose of this study is to evaluate the spread of using both ACEIs and ARBS together in Saudi hospitals. The present study is to estimate the adherence to risk minimization measures implemented by Saudi Food and Drug Authority (SFDA). This research use measures taken by SFDA targeting to reduce the concomitant administration of ACE and ARBs. The main Objective of this study to estimate the prevalence of ACEIs and ARBs in concomitant use for hypertensive patients over years.
MATERIALS AND METHODS
Study design, data source and patient population
A retrospective study using the Electronic Health Records (EHRs) imported and mapped from a several hospitals in Saudi Arabia. All the patients who visited the hospital in the period between 2016 till the end of 2022 and received at least one drug from the category ACE inhibitors or angiotensin receptor blockers will be included for the study.
Inclusion criteria
a. Patients with minimum one oral antihypertensive medication from the category of ACE inhibitors or AR blockers.
b. Patients 18 years or older.
Exclusion criteria
Patients received ACE inhibitors and AR blockers other than hypertension were not included in the study.
Method of data collection
The data were collected from the Real-world Evidence Research Network available at Saudi Food and Drug Authority. The recorded data were included like demographic variables and treatment regimens.
Variables of the study
Patient characteristics, including socio-demographic factors (Age, sex), concomitant use of medication and treatment episodes for individual and concomitant therapy, were included in the study. The prevalence of concomitant use of ACE inhibitors and AR blockers were calculated as number of patients in the sample with the characteristic of interest, divided by the total number of patients in the sample. Incidence rate per 10000-patient years were calculated as number of episodes of each category of drugs in a year divided by exposures in years multiple with 10000.
Statistical analysis
Patient characteristics were summarized using descriptive statistics for categorical variables. The age of the participants was calculated by the median interquartile range. The data were analyzed using Statistical Package for the Social Sciences (SPSS) version 24. Statistical significance was set at p<0.05.
Ethical approval
The research proposal was approved by Institutional Review Board, Research Center, Riyadh ELM University with the IRB approval number “FPGRP/2023/771/1034/935” and Saudi Food and Drug Authority, KSA with the approval number 2023_8.
RESULTS
Prevalence of ACE inhibitors and ARBs use
The total number of patients included in the study is 106034. 54071 patients were male (50.9%) and 51963 patients were female (49.1%) with median age of the patients is 61 and IQR 18. 1631419 prescriptions were given to these patients from 2016 to 2022. The percentage of prescriptions used for ACEI was 55.1% (899302) and 44.9% (732117) for ARBs of the total number of medical prescriptions during this period (1631419).
The average duration of use for the group ACEIs was approximately 101932 times and for ARBs Group about 90643 times overall years, (Table 1) (Figure 1).
| All | ACEIs | ARBs | ||||
|---|---|---|---|---|---|---|
| N | % | N | % | N | % | |
| Number of prescriptions | 1631419 | 100% | 899302 | 55.1 | 732117 | 44.9 |
| Total number of patients | 106034 | |||||
| Total exposure time (years) | 192575 | 101932 | 90643 |
Name of the drug for ACEIs and ARBs
Table 2 illustrated the most common drug for ACEIs and ARBs from 2016 to 2022. Through the aforementioned period, it was found that the most common medications used in ACEIs group were Captopril, Enalapril, Fosinopril, Perindopril, Lisinopril, Ramipril and Quinapril with different doses, while the most common medications used from ARBs group were Olmesartan, Candesartan, Irbesartan, Eprosartan, Losartan, Telmisartan, Valsartan, (Table 2).
| ACEIs | ARBs |
|---|---|
| Captopril | Olmesartan |
| Enalapril | Candesartan |
| Fosinopril | Irbesartan |
| Perindopril | Eprosartan |
| Lisinopril | Losartan |
| Ramipril | Telmisartan |
| Quinapril | Valsartan |
Number of prescriptions in each year
Table 3 showed the number of prescriptions for ACEI Group and ARBs Group were used during each year. For ACEIs group, the survey illustrated that the most frequent use of prescriptions was in 2019 with 18.9%, followed by 2018 (16.7%), year 2020 with 15.1%, 2017 year with 14.6% and 2022 with14.3% while we find that the least number of times used was in 2016, with 8.6%. On the other hand, for ARBs groups, we find that the most frequent years in which prescriptions were used was 2018 with a ratio of 18.7%, followed by 2019 with 17.9%, 2017 with ratio 16.6% while the lowest years were recorded in year 2016, (Figure 2).
| years | ACEI | ARBs | |||
|---|---|---|---|---|---|
| N | % | N | % | ||
| Number of Prescriptions per Year | 2016 | 139891 | 8.6 | 87181 | 9.7 |
| 2017 | 237494 | 14.6 | 149602 | 16.6 | |
| 2018 | 272261 | 16.7 | 168030 | 18.7 | |
| 2019 | 308407 | 18.9 | 160755 | 17.9 | |
| 2020 | 246380 | 15.1 | 128966 | 14.3 | |
| 2021 | 194466 | 11.9 | 97549 | 10.8 | |
| 2022 | 232520 | 14.3 | 107219 | 11.9 | |
| Total | 1631419 | 100% | 899302 | 100% |
The Concomitant Use ACEIs & ARBs during 2016 to 2022
Table 4 shows Concurrent Use of ACEIs and ARBs from 2016 to 2022. The study showed that the total number of patients Concurrent Use of ACEIs and ARBs during these periods was 2706 patients (2.6% of total number of patients). The highest percentage of Concurrent Used was recorded in the females with 56.7%, while in the males was 43.3% and the median age of the patients was 61 years and IQR (18), (Figure 3).
| Concomitant Use ACEIs & ARBs | No Concomitant Use | |
|---|---|---|
| Number of patients | 2706 (2.6%) | 103328 (97.4%) |
| Gender | ||
| Male | 1172 (43.3%) | 52899 |
| Female | 1534 (56.7%) | 50429 |
| Median Age (IQR) | 61 (18) | 60 (19) |
The number of exposure times during the 2016 to 2022
Table 5 illustrated the number of exposure times during the 2016 to 2022, The results of the inventory process showed that the year 2019 was the most frequent for the number of exposure time with 19.4% from the total number of exposure times, followed by 2018 (17.6%), year 2017 (15.5%), year 2020 (14.2%) and year 2022 (13.7%), while the years 2016 and 2021 were the least years for the number of exposure times, with 9.3% and 10.3%, respectively, (Figure 4).
| exposure time (N) | % | |
|---|---|---|
| Overall | 193054 | 100% |
| 2016 | 18000 | 9.3% |
| 2017 | 30000 | 15.5% |
| 2018 | 34000 | 17.6% |
| 2019 | 37500 | 19.4% |
| 2020 | 27342 | 14.2% |
| 2021 | 19800 | 10.3% |
| 2022 | 26412 | 13.7% |
Number of Episodes and Incidence rate per 10000-patient years
Table 6 showed the Number of episodes and incidence rate from 2016 to 2022. Regarding the number of episodes, we found the year 2019 was the most (604), followed by the year 2018 (563), then the year 2017 (543), the year 2022, but the least years for the Number of episodes were the year 2020, 2016 and 2021. As for the Incidence rate per 10000-patient years, the year 2016 was the most year for the Incidence rate, followed by the year 2017, then the year 2022, 2018 and 2019, and finally the least years were the year 2021and 2020, (Figure 5).
| Years | Number of Episodes | Incidence rate per 10000-patient years |
|---|---|---|
| Overall | 3196 | 166 |
| 2016 | 349 | 194 |
| 2017 | 543 | 182 |
| 2018 | 563 | 167 |
| 2019 | 604 | 161 |
| 2020 | 391 | 143 |
| 2021 | 297 | 150 |
| 2022 | 449 | 170 |
DISCUSSION
The current retrospective has identified a notable prevalence of concomitant use of Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs). This percentage reflects a similar trend in the utilization of these drugs as has been reported in other studies.
However, it is imperative to consider the implications of our findings against the backdrop of existing literature. Previous research has raised concerns about the risk of adverse events such as kidney dysfunction and hyperkalemia with the concurrent use of ACEIs and ARBs.
This study's primary objective was to ascertain the prevalence of concomitant ACE inhibitor (ACEI) and Angiotensin Receptor Blocker (ARB) use and its clinical implications. We analyzed data from 106,034 patients, revealing that 55.1% of the 1,631,419 prescriptions issued between 2016 and 2022 were for ACEIs and 44.9% for ARBs. A substantial finding was the proportion of concomitant usage among these prescriptions, which stood at a notable prevalence, highlighting a prevalent prescribing pattern that differs from the cautionary stance observed in earlier studies.
Notably, the concomitant use of ACEIs and ARBs was 2.6% the patients, with a higher prevalence in females (56.7%) compared to males (43.3%). This figure sheds light on the persistence of combined therapy despite known risks. Our results indicate a distinct contrast to studies like those by Philips et al, 2011, which suggested limited benefits and heightened risks associated with such combination therapies.
Furthermore, our study's findings on the distribution of concomitant therapy across different years with the highest usage in 2019 provide new insights into prescribing trends, which have not been extensively covered in previous literature. This temporal analysis is particularly relevant given the ongoing debates about the safety and efficacy of ACEIs and ARBs in combination therapy (Almutlaq et al., 2021).
In comparison with previous research, our study offers updated insights into prescribing behaviors and prevalence rates, adding a contemporary layer to the understanding of ACEI and ARB use in a large patient population. It underscores the need for further prospective studies to understand the full clinical impact of concomitant ACEI and ARB therapy, especially in light of the diverse findings from past studies that range from highlighting potential benefits to indicating severe risks" (Herman et al., 2023).
The limitation of our study lies in its observational nature and the potential for underreporting or misclassification of medication use, which could lead to an underestimation or overestimation of the true rate of concomitant use. Furthermore, our study does not account for potential confounders such as the severity of disease, the duration of treatment, or the presence of comorbid conditions, which may influence the outcomes of interest.
Despite these limitations, our findings contribute valuable insights into the current practices surrounding the use of ACEIs and ARBs and highlight the need for rigorous monitoring when these medications are used together. Future research should aim to quantify the risks and benefits of this treatment approach more precisely, guiding clinicians in optimizing therapy for patients with chronic kidney disease and cardiovascular condition (Parikh et al., 2020).
CONCLUSION
In the present study, the findings concluded that the prevalence of concomitant use is still detected but at a low rate reflecting that the implementation of risk reduction measures by the Saudi Food and Drug Authority has been adhered to by most doctors during practice. However, the adherence rate still needs to be increased to reach a zero percentage of concomitant use of ACEIs and ARBs among hypertension patients.