Association between Drug-Related Problems and Blood Pressure of Hypertensive Patients Admitted to Universitas Sumatera Utara Hospital

health centers in Medan, Indonesia, was conducted. This study identified 66 DRPs experienced by nearly half (45.8%) of the patients 9 . Additionally, a study on DRPs conducted in a tertiary hospital in Malaysia found 387 DRPs in 200 patients with hypertension with type 2 diabetes mellitus 10 . Identification and analysis of DRPs are essential to improve the management and outcomes of hypertensive


INTRODUCTION
Hypertension is a chronic disease that affects 600 million people worldwide, with an annual mortality of 12.8% 1 . In 2025, hypertension cases are estimated to increase to around 80%. Increased cases of hypertension also occur in Indonesia. Fact indicated that hypertension cases increased from 25.8% in 2013 to 34.1% in 2018 2 . Hypertension must be controlled to avoid further complications such as heart disease, stroke, kidney failure, eye disorders, and even pose a risk of premature death. Therefore, appropriate pharmacological therapy is crucial to obtain the desired outcomes 3 . Hypertensive patients require complex medical therapy because they generally have chronic comorbidities 4 . This condition can eventually lead to drug-related problems (DRPs) 5 . Drug-related problems in hypertensive patients can result in ineffective treatment, further interfering with the desired clinical outcome 6 . Uncontrolled blood pressure (BP) can increase the risk of complications such as heart failure, kidney failure, and cerebrovascular disease 7 . These DRPs could also decrease the patient's quality of life (QoL). The low QoL of hypertensive patients is influenced by uncontrolled systolic and diastolic BPs, obesity, complications in target organs, the number of antihypertensive drugs used, and side effects 8 . Several studies on the incidence of DRPs in hypertensive patients have been conducted. A study on the incidence of DRPs in managing hypertensive patients (n=107) admitted to four primary health centers in Medan, Indonesia, was conducted. This study identified 66 DRPs experienced by nearly half (45.8%) of the patients 9 . Additionally, a study on DRPs conducted in a tertiary hospital in Malaysia found 387 DRPs in 200 patients with hypertension with type 2 diabetes mellitus 10 . Identification and analysis of DRPs are essential to improve the management and outcomes of hypertensive

Abstract
Patients with hypertension usually experience chronic comorbidities and complications that require complex treatment (polypharmacy), which can further cause drug-related problems (DRPs) and interfere with the required clinical outcomes. This study, by using a case-control prospective cross-sectional, aimed to analyze the association between DRPs and blood pressures (BPs) of hypertensive patients admitted to Universitas Sumatera Utara (USU) hospital from July to September 2021. The incidence of DRPs was analyzed and classified according to the Cipolle classification system and reliable literature. Blood pressures of the patients were classified into controlled and uncontrolled BPs. The association between DRPs and BP was analyzed using the Chi-Square test. Most of the patients (57.5%) were female. Their mean age was 59±9.94 (years). The mean incidence of DRPs experienced by the patients was 1.78±0.79. The most frequently occurred DRPs were drug interactions. There was a significant association between the number of DRPs experienced by the patients and their BPs (p=0.02). DRPs are the contributing factor to the uncontrolled BPs of hypertensive patients.

Materials
This prospective cross-sectional analytical study was conducted to analyze the association between DRPs and clinical outcomes of hypertensive patients admitted to Universitas Sumatera Utara Hospital, period July to September 2021. This study involved 120 hypertensive patients who met the inclusion criteria: patients diagnosed with hypertension for more than three months; aged 18 years or older with or without comorbidities and complications; and willing to participate in this study with evidence of their willingness to sign an informed consent. Exclusion criteria were pregnant and breastfeeding patients, patients with Human Immunodeficiency Virus/acquired immunodeficiency syndrome (HIV/AIDS), and tuberculosis (TBC). This research was approved by the Health Research Ethics Committee, Faculty of Medicine, Universitas Sumatera Utara, Medan.

Study design
The identification and classification of DRPs were carried out using the Cipolle DRPs classification system, and reliable 11,12 . Some points need to be mentioned with Cipolle DRPs in specific classifications, such as intervention acceptance and status of DRPs that can't be stated. The patients' BPs were assessed from their medical records and stratified into controlled and uncontrolled groups based on JNC 8 guidelines for hypertension algorithm 13 . The patients were also stratified according to the number of DRPs that they encountered.

Statistical analysis
The association between DRPs and the patients' BPs was statistically analyzed using the Chi-Square test in the SPSS program version 22.0 (p <0.05 was considered significant).

Patient characteristics
Characteristics of the patients with hypertension are listed in Table I. Most of the patients (57.5%) were females. The mean age of the patients was 59±9.937 (years). Of the 120 patients, 48 (40%) were 61-70 years old. Nearly half of them (45%) graduated from high school, and as many as 112 patients (93.4%) had comorbidities.

DRPs incident and relationship with clinical outcome
The incidence of DRPs in managing hypertensive patients was classified into controlled and uncontrolled groups, as listed in Table II  According to Table III, the first identified DRPs in this group of patients were the category of unnecessary therapy. Only 4.3% of the patients experienced unnecessary therapy in the controlled group, and 4% experienced unnecessary drug therapy in the uncontrolled group. These patients were prescribed drugs not indicated, including gabapentin, simvastatin, cetirizine, diclofenac sodium, allopurinol, and omeprazole. The second detected DRP category was an additional drug needed by the patients. In the controlled BP group, only one patient (1.4%) required additional drugs, and the patient experienced vertigo, but no medication was provided to treat the symptoms. The patient experience obtained from previous prescription treatment or medical records is categorized as inpatients; therefore, the status of DRPs can't be described with the use of the Cipolle method. None of the patients in the uncontrolled group experienced this DRPs category. This study found that 22.8% of the patients experienced ineffective therapy in the controlled group. Only one patient (2%) experienced DRPs in the uncontrolled BP group. Few patients received antihypertensive combinations when their BP reached the therapeutic target (<140/90 mmHg). According to the JNC 8 hypertension guideline algorithm 13 , the main goal of hypertension treatment is to achieve and maintain BP targets. If the target BP is not achieved within one month of treatment, the initial dose may be increased, or a second drug from other classes may be added (thiazide diuretic, CCB, ACEI, or ARB) 14 . A similar study 15 conducted on 90 hypertensive patients at the Yogyakarta Health Center found a significant association between DRPs and BP targets for hypertensive patients (p <0.05). In this case, the presence of DRPs failed to achieve the BP target. With regard to the under-dose problem, none of the patients in the control group experienced this problem. However, five patients (10%) experienced under-dose problems in the uncontrolled group. They were prescribed amlodipine with the lowest dosage strength (5 mg). According to the JNC 8 hypertension guideline algorithm 13 , the dose of antihypertensive drugs can be increased if the patient's BP does not show a significant decrease within one month of therapy. Many factors can affect the successfulness in the management of hypertensive patients, such as the accuracy of drug selection based on the patient's condition, the dose of the drug given, psychological factors such as the presence of white coat hypertension characterized by the patient's fear while in the hospital dealing with doctors or nurses causing higher BP compared to those measured in the patient's typical environment [16][17][18] . In addition to pharmacological therapy, the patients must be educated to practice non-pharmacological approaches 19 . The following identified DRP was a drug overdose. Two patients (2.8%) in the control group experienced drug overdose. These patients were given a combination of amlodipine and telmisartan. During the treatment period, the patients' BPs were below standard. None of the patients experienced drug overdose in the uncontrolled BP group. Even though these combinations are recommended due to their excellent efficacy in reducing BPs, the patients' BPs were below the normal value due to the interaction between these antihypertensive drugs 20 . Thus, close monitoring of these patients is crucial. The last DRP identified was drug interactions. Drug interactions were the most frequently identified incidence, reaching 183 events (86.1%). In the controlled BP group, 41 patients (58.6%) experienced 123 drug interactions. In the uncontrolled BP group, 36 patients (72%) experienced 60 drug interactions. This finding is in line with a study conducted by Hussein et al. 21 at Adama Hospital Medical College, East Ethiopia, in which the most frequently occurring DRPs were drug interaction categories that reached 58.7%. The results showed that hypertensive patients were susceptible to DRPs due to various factors such as polypharmacy that they received, comorbidities that they experienced, and also their ages. This study found that, on average, each patient was prescribed eight different drugs. The high number of drugs provided to the patients has the possibility for DRPs to occur, which can interfere with the clinical outcomes 22,23 . The grouping of DRPs based on the number of incidences experienced by 92 hypertensive patients is listed in Table IV. The number of DRPs experienced by hypertensive patients varies from 1 to 8. The three highest incidences by number were 1, 2, and 3 DRPs experienced by 42, 20, and 12 hypertensive patients, respectively. There was a significant association between the number of DRPs and the mean BP of the hypertensive patients (p=0.02). The higher the number of DRPs experienced by hypertensive patients, the higher the patients' BPs 24 . This study proved a significant association between the number of DRPs and the mean BP of hypertensive patients. Other similar studies have been conducted elsewhere, including a retrospective cross-sectional study at the Gondar University Hospital in Ethiopia. They found that variation in DRPs occurrence was significantly associated with controlled and uncontrolled BPs in hypertensive patients 25 . Drug-related problems are a significant challenge for healthcare providers in managing hypertensive patients. The incidence of DRPs can interfere with the required patients' clinical outcomes, directly affecting the patient's QoL. Thus, rationality in prescribing drugs to patients with hypertension is critical in improving their clinical outcomes and QoL 6,24 .

CONCLUSION
The incidence of DRPs in managing hypertensive patients admitted to the Universitas Sumatera Utara Hospital was still high. The highest DRP incidence experienced by hypertensive patients was drug interaction. Drug-related problems contributed significantly to the failure to achieve the BP target. Efforts should always be made to minimize these problems and optimize the patient's clinical outcomes.