INTRODUCTION

Globally, 1.28 billion adults in the age group of 30-79 years have hypertension and 66% of them are in low and middle-income countries. Of these, only 21% have their blood pressure under control¹. In the Southeast Asia Region where 25% of adults have hypertension, only one in three are treated and only 10% have their hypertension under control². Hypertension is defined as a systolic blood pressure of >= 140 mmHg or a diastolic pressure of >= 90 mmHg^1,3. Despite advances in medical therapy, hypertension remains a major risk factor for stroke, heart failure, renal failure, atherosclerosis, and dementia⁴. In Bhutan, there are 352.4 people per 10,000 population (3.52%) with hypertension, an increase from 301.2/10,000 (3.01%) in 2019⁵. Among other complications, hypertension (20.85%) was the most common cause of end stage renal disease in Bhutan⁶.

The treatment and control of hypertension is essential to prevent the development of complications, as well as control the worsening of associated complications. Similarly, patients’s optimal adherence to anti-hypertensive drugs is essential to prevent complications of hypertension⁷. Effective hypertension management and compliance with medications will bring about

better health and economic benefits. It will reduce burdens on acute-care services, increase the integration of health care systems, and most importantly, reduce deaths, suffering, and costs arising from complications such as heart failure, stroke and kidney failure¹. Patients often require a combination of antihypertensive drugs for the control of hypertension.

Although there are several guidelines for treating hypertension such as the Joint National Committee guideline, WHO guidelines for the pharmacological treatment of hypertension in adults and the recent hypertension protocol of Bhutan, clinicians may not be aware of the latest updates on treatment guidelines^3,8,9. These could lead to outdated prescription practices and suboptimal control of blood pressure leading to complications of hypertension.

Over 10 antihypertensive drugs of various classes are available for prescription in Bhutan. The objective of the study was to characterize the current prescribing patterns of antihypertensive drugs.

METHODS

Study design

This cross-sectional study was carried out at the outpatient departments of JDWNRH over a period of nine months spanning 18 April 2023 to 31 December 2023.

Study setting

JDWNRH is the apex tertiary teaching hospital in Bhutan, where 593,290 patients were seen in the outpatient department in 2023¹⁰. The hospital has 1,530 staff with 20 clinical departments. The departments provide general clinical services as well as superspeciality services including cardiology, nephrology, gastroenterology, maternal fetal medicine, urology, neurosurgery, pediatric surgery, and pediatric ophthalmology among others.

Study participants

The study included patients over the age of 18 years who were on antihypertensive treatment. Patients under the age of 18 years, pregnant women, and those with comorbidities were excluded from the study.

Data collection

The prescriptions of patients who were diagnosed with hypertension and on antihypertensive drugs were retrieved from the electronic Patient Information System (ePIS). ePIS is a system for recording, storing and sharing patient information for patient care, research and quality management through an online electronic system. The system was launched at JDWNRH on 18 April 2023 and is being rolled out to other hospitals. Details including demographic information, names of antihypertensive medications and blood pressure readings were extracted by the author from the ePIS record.

Data analysis

Data was checked for duplication by using Microsoft Excel and analyzed using SPSS version 25. Demographic information of patients is presented as percentages, median, and mean values. The types of drugs prescribed and the proportion of controlled blood pressure are analysed as frequencies and percentages. The significance of the association of blood pressure control between females and males and between monotherapy and combination therapy was determined using a chi square test, with a p value of < 0.05 being statistically significant.

Ethical clearance

Ethical clearance was obtained from the Institutional Review Board of KGUMSB (IRB/Approval/PN/2023-021/1134). Administrative clearance for the study was obtained from Ministry of Health and JDWNRH.

RESULTS

A total of 1150 prescriptions were obtained for the study, where 61.65 % were females. The median age was 55 years with a range of 19-94 years. Nearly 40% of the patients were above the age of 60 (Table 1).

More than half of the patients were treated with monotherapy (59.1%), followed by dual therapy (36.3%) as depicted in Table 2. Among the antihypertensive regime, losartan is the most prescribed drug (45.9%) among the monotherapy drugs and a combination of losartan with amlodipine is the most frequent drug prescribed for dual therapy (16.2%). The combination of losartan, hydrochlorothiazide, and amlodipine was prescribed most frequently (1.7%) in the triple therapy group (Table 3).

Table 1. Demographics of patients taking antihypertensive drugs at JDWNRH outpatient departments, 2023.

Age group (years)	Females n(%)	Males n(%)
15-19	1 (0.09)	0 (0)
20-24	4 (0.35)	2 (0.17)
25-29	5 (0.43)	10 (0.87)
30-34	25 (2.17)	11 (0.96)
35-39	68 (5.91)	16 (1.39)
40-44	76 (6.61)	39 (3.39)
45-49	91 (7.91)	62 (5.39)
50-54	117(10.17)	44 (3.83)
55-59	68 (5.91)	60 (5.22)
60-64	64 (5.57)	53 (4.61)
65-69	70 (6.09)	46 (4.00)
70-74	66 (5.74)	42 (3.65)
75-79	41 (5.57)	26 (2.26)
80-84	8 (0.70)	21 (1.83)
85-89	3 (0.26)	8 (0.70)
90-94	2 (0.17)	1 (0.09)
Total	709 (61.65)	441 (38.35)

Table 2. Distribution of antihypertensive drug therapy prescribed to hypertensive patients during the study period at JDWNRH in 2023.

Therapy type	N (%)
Mono Therapy	680 (59.1)
Dual Therapy	417 (36.3)
Triple Therapy	50 (4.3)
Multi Therapy	3 (0.3)
Total	1150 (100)

Table 3. Prescription pattern of antihypertensive drugs among hypertensive patients during the study period at JDWNRH in 2023.

Antihypertensive drugs	Number of patients n (%)
Monotherapy
Losartan	528 (45.9)
Hydrochlorothiazide	73 (6.3)
Amlodipine	38 (3.3)
Nifedipine	22 (1.9)
Enalapril	7 (0.6)
Propranolol	7 (0.6)
Atenolol	3 (0.3)
Carvedilol	1 (0.1)
Hydralazine	1 (0.1)
Dual therapy
Losartan, amlodipine	186 (16.2)
Losartan, hydrochlorothiazide	123 (10.7)
Losartan, nifedipine	59 (5.1)
Losartan, propranolol	16 (1.4)
Nifedipine, hydrochlorothiazide	6 (0.5)
Losartan, atenolol	5 (0.4)
Amlodipine, enalapril	5 (0.4)
Losartan, metoprolol	3 (0.3)
Losartan, carvedilol	2 (0.2)
Losartan, enalapril	2 (0.2)
Nifedipine, metoprolol	2 (0.2)
Hydrochlorothiazide, amlodipine	2 (0.2)
Hydrochlorothiazide, propranolol	2 (0.2)
Losartan, captopril	1 (0.1)
Amlodipine, carvedilol	1 (0.1)
Amlodipine, hydralazine	1 (0.1)
Amlodipine, propranolol	1 (0.1)
Enalapril, atenolol	1 (0.1)
Triple therapy
Losartan, hydrochlorothiazide, amlodipine	20 (1.7)
Losartan, nifedipine, hydrochlorothiazide	7 (0.6)
Losartan, amlodipine, propranolol	3 (0.3)
Losartan, nifedipine, atenolol	2 (0.2)
Losartan, hydrochlorothiazide, propranolol	2 (0.2)
Losartan, amlodipine, metoprolol	2 (0.2)
Losartan, nifedipine, atenolol	1 (0.1)
Losartan, hydrochlorothiazide, hydralazine	1 (0.1)
Losartan, hydrochlorothiazide, enalapril	1 (0.1)
Losartan, hydrochlorothiazide, metoprolol	1 (0.1)
Losartan, hydrochlorothiazide, atenolol	1 (0.1)
Losartan, amlodipine, carvedilol	1 (0.1)
Losartan, amlodipine, atenolol	1 (0.1)
Losartan, enalapril, carvedilol	1 (0.1)
Nifedipine, amlodipine, carvedilol	1 (0.1)
Nifedipine, amlodipine, captopril	1 (0.1)
Hydrochlorothiazide, amlodipine, atenolol	1 (0.1)
Hydrochlorothiazide, enalapril, carvedilol	1 (0.1)
Amlodipine, atenolol, propranolol	1 (0.1)
Multiple therapy
Losartan, hydrochlorothiazide, amlodipine, metoprolol	2 (0.2)
Losartan, nifedipine, hydrochlorothiazide, propranolol	1 (0.1)
Total	1150 (100)

Among those patients on medications, 42.45% of the patients had their blood pressure under control. Blood pressure control is defined as systolic blood pressure and diastolic blood pressure <140/90 mmHg. There was no significant difference in the blood pressure control between patients receiving monotherapy or combination therapy, neither between females and males on antihypertensive drug treatment (Table 4).

Table 4. Blood pressure control among hypertensive patients, by types of therapy and gender, visiting outpatient departments of JDWNRH, 2023.

Status of Blood pressure	Controlled n (%)	Uncontrolled n (%)	Chi- square	p-value
Types of therapy
Combination therapy Monotherapy	163 (16.40)	243 (24.44)
Combination therapy Monotherapy	259 (26.06)	329 (33.10)	1.495	0.221
Gender
Male Female	157 (15.79)	219 (22.03)
Male Female	265 (26.66)	353 (35.51)	0.121	0.728

DISCUSSION

Herein, we report a case of locally advanced SCC of the cervix (FIGO IIIB) in an 83-year-old woman who was diagnosed as benign ovarian tumor preoperatively, but intraoperatively diagnosed to have a hydrometra and hydrocolpos with left hydroureter secondary to locally advanced cervical cancer.

Having presented with abdominal pain and distension, the clinical examination of abdomen was in favor of a benign abdomino-pelvic mass. CT images were reported as a bilateral ovarian cyst and tumor markers were within normal range, which led to the diagnosis of a benign ovarian tumor preoperatively. Intra-operatively, hydrometrocolpos with a large cervical growth, obliterating the left distal ureter was noted. Furthermore, there was complete adhesion of vaginal walls, which must have caused secondary hydrocolpos. She never had cervical cancer screening in her lifetime, because she was embarrassed to expose her private parts for examination by health workers. This is a common scenario in Bhutan, where a study has reported that 40.8% of its study participants were never screened for cervical cancer, and women aged <35 years or > 45 years diagnosed with cervical cancer were associated with a lack of previous screening⁵. The national cervical cancer screening of Bhutan recommends women between 30-65 years to be screened every 5 years with HPV-DNA test⁶.

There is a case report of a patient with multiple lymphadenopathies without local symptoms of cervical cancer who was diagnosed as locally advanced cervical cancer (FIGO IIB). The cervical growth was detected by ¹⁸F-Fluoro deoxy glucose (FDG) positron emission tomography/computed tomography ( ¹⁸F-FDG PET/CT) which showed focal hypermetabolic heterogeneously enhancing soft tissue mass in the uterine cervix⁷. An epidemiological study has reported that greater hydrometra volume (distance between the two layers of endometrium >4.75mm) is a high-risk predictive factor for uterine and cervical cancers⁸. However, to the best of our knowledge, there is no report of locally advanced cervical cancer that was diagnosed in a patient without any gynaecologic symptoms who presented with hydrometrocolpos.

Univariate and multivariate analysis has reported that advanced age (OR 1.11) and vaginitis (OR 3.18) are independent risk factors for hydrometra⁸. Inflammation is regarded as the most important cause, especially in post-menopausal women, and it is rare in premenopausal women. In our case, the hydrometra could have resulted from cervical stenosis secondary to obstruction of cervical canal by the locally advanced cervical cancer, and the hydrocolpos probably resulted from total upper vaginal stenosis secondary to vaginitis. Her age being 83 years is an independent risk factor for hydrometra.

Carcinoma of cervix that has extended to the pelvic side wall and/or hydronephrosis or non-functioning kidney (unless known to be due to another cause) is staged IIIB as per 2018 FIGO staging of the cervix uteri⁹. For FIGO IIIB SCC, the National Comprehensive Cancer Network recommends pelvic external beam radiation therapy (EBRT) with concurrent platinum containing chemotherapy with brachytherapy¹⁰. ESGO/ESTRO/ESP recommends EBRT with concurrent chemotherapy with image guided brachytherapy¹¹. In our case, a simple hysterectomy with resection of distal left ureter was an intentional intra-operative decision, despite the surgeon being aware of under treatment for cervical cancer, and the disadvantages of combined treatment with surgery and radiation. The main aim was to resect the involved ureter to prevent obstructive uropathy. Primary anastomosis of ureter with bladder was performed without complications of anastomotic leakages. If FIGO IIIB cervical cancer with hydrometrocolpos was diagnosed preoperatively, the treatment would have been drainage of hydrometrocolpos and relief of left hydroureteronephrosis followed by definitive EBRT with concurrent chemotherapy, and vaginal brachytherapy.

In the postoperative period, the patient was convinved for the need of definitive treatment with radiation and chemotherapy. She was planned to undergo definitive EBRT without concurrent chemotherapy, followed by vaginal brachytherapy.

CONCLUSION

In this case, hydrometrocolpos secondary to locally advanced cervical cancer was misdiagnosed as a benign ovarian tumour preoperatively. Radiologists have an important role in providing an accurate radiological diagnosis, so that proper treatment is planned. In an elderly woman presenting with abdomino-pelvic mass, with a stenosed vagina and hydroureteronephrosis, gynecologists need to be aware of the possibility of locally advanced cervical cancer and plan relevant pre-operative assessments.

Acknowledgement: We would like to thank Dr Sonam Dargay, Consultant Urologist at the Jigme Dorji Wangchuck National Referral Hospital, for his help in performing primary anastomosis of left ureter with bladder with DJ stent in situ. We are indebted to our patient, who kindly permitted us to use her de-identified clinical details and images for publication.

REFERENCES

1. World Health Organization. Hypertension. World Health Organization. 2023 [Full Text ]

2. World Health Organization. Scale-up efforts to prevent, detect and control hypertension. World Health Organization. 2023 [Full Text ]

3. World Health Organization. Guideline for the pharmacological treatment of hypertension in adults. World Health Organization. 2021. 48p [Full Text ]

4. Harrison DG, Coffman TM, Wilcox CS. Pathophysiology of Hypertension. Circ Res. 2021; 128(7):847–63. [Pub Med ] [Full Text ] [DOI ]

5. Ministry of Health, Bhutan. Annual Health Bulletin 2024. Ministry of Health. 2024; 175p. [Full Text ]

6. Dorji M, Penjore Y, Tshokey T, Dorji G. Aetiology of endstage renal disease at the National Referral Hospital of Bhutan. Bhutan Health J. 2023; 9(1):1–5. [Full Text ] [DOI ]

7. Chandra S, Ubale A, Bhosle D, Jayabhaye D, Kaur S. A study of prescription pattern of the pharmacotherapy of patients of hypertension at a tertiary care hospital, Aurangabad,Maharashtra, India. Int J Basic Clin Pharmacol. 2019; 8(7):1599. [Full Text ] [DOI ]

8. James PA, Oparil S, Carter BL, Cushman WC, DennisonHimmelfarb C, Handler J, et al. Evidence-Based Guideline for the Management of High Blood Pressure in Adults. 2014; 311(5):507 - 20. [Full Text ] [DOI ]

9. Ministry of Health, Bhutan. Hypertension Management Protocol. Ministry of Health. 2023. 1p [Full Text ]

10. Jigme Dorji Wangchuck National Referral Hospital. Annual Report 2023. 139p. [Full Text ]

11. Ministry of Health, Bhutan. 5th National Health Survey. Ministry of Health. 2023. 21p. [Full Text ]

12. Kedare RK, Pujari AJ, Hivale N, Kharat R. Antihypertensive drug prescription patterns and their impact on blood pressure outcomes in a tertiary care teaching hospital. Int J Basic Clin Pharmacol. 2024;13(4):502–5. [Full Text ] [DOI ]

13. Lionakis N, Lionakis N, Mendrinos D, Sanidas E, Favatas G, Georgopoulou M. Hypertension in the elderly. World J Cardiol. 2012; 4(5):135-47. [Pub Med ] [Full Text] [DOI ]

14. Kapil U, Khandelwal R, Ramakrishnan L, Khenduja P, Gupta A, Pandey R, et al. Prevalence of hypertension, diabetes, and associated risk factors among geriatric population living in a high-altitude region of rural Uttarakhand, India. J Fam Med Prim Care. 2018;7(6):1527. [Pub Med ] [Full Text] [DOI ]

15. Rajasekhar DG, Prasanna DG, Chandrakanth P. Prescribing pattern of antihypertensive drugs based on compelling indications with hypertension. Int J Pharm Pharm Sci. 2016; 8(2):72–5. [Full Text ]

16. Liu PH, Wang JD. Antihypertensive medication prescription patterns and time trends for newly-diagnosed uncomplicated hypertension patients in Taiwan. BMC Health Serv Res. 2008;8(1):133. [Pub Med] [Full Text ] [DOI ]

17. Kim SH, Shin DW, Kim S, Han K, Park S, Kim YH, et al. Prescribing Patterns of Antihypertensives for TreatmentNaïve Patients in South Korea: From Korean NHISS Claim Data. Int J Hypertens. 2019;2019(1):4735876. [Pub Med ] [Full Text ] [DOI ]

18. Setia S, Subramaniam K, Tay JC, Teo BW. Hypertension and blood pressure variability management practices among physicians in Singapore. Vasc Health Risk Manag. 2017 Jul;Volume 13:275–85. [Pub Med ] [Full Text ] [DOI ]

19. Alkaabi MS, Rabbani SA, Rao PGM, Ali SR. Prescription Pattern of Antihypertensive Drugs: An Experience from a Secondary Care Hospital in the United Arab Emirates. J Res Pharm Pract. 2019 Jun;8(2):92-100. [Pub Med] [Full Text] [DOI ]

20. Ikeda N, Sapienza D, Guerrero R, Aekplakorn W, Naghavi M, Mokdad AH, et al. Control of hypertension with medication: a comparative analysis of national surveys in 20 countries. Bull World Health Organ. 2013 Sep 30;92:10-19C. [Pub Med ] [Full Text ] [DOI ]

21. Shanmugapriya S, Thangavelu S, Shukkoor A, Janani P, Monisha R, Scaria V. Prescribing patterns and pharmacoeconomic analysis of antihypertensive drugs in South Indian population: A cross-sectional study. Perspect Clin Res. 2023;14(3):114-22. [Pub Med ] [Full Text] [DOI ]

22. Wang W, Tang J, Hu Y, An J, Wang Y, Ren Z, et al. Gap between evidence and physicians’ knowledge and practice regarding hypertension and its drug treatment: a survey in a Chinese city. Chin Med J (Engl). 2011; 124(8): 1235-41. [Pub Med ] [Full Text]

23. Touyz RM, Schiffrin EL. A Compendium on Hypertension: New Advances and Future Impact. Circ Res. 2021 Apr 2;128(7):803–7. [Full Text ] [DOI ]

24. Selvaskanthan K, Ghetheeswaran S, Kumanan T, Rajeshkannan N. A descriptive study on prescription pattern of antihypertensive medications in a tertiary care hospital in Northern Sri Lanka. Sri Lanka J Med. 2021 Dec 30;30(2):156. [Full Text ] [DOI ]

ABSTRACT: