A Multi-Centric Study of Real-World Prescription Pattern of More Than Three Drugs for the Control of Hypertension Among Cardiologists

A Multi-Centric Study of Real-World Prescription Pattern of More Than Three Drugs for the Control of Hypertension Among Cardiologists | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A Multi-Centric Study of Real-World Prescription Pattern of More Than Three Drugs for the Control of Hypertension Among Cardiologists Prabhakar Dorairaj, Shanmugasundaram Somasundaram, Sunny Nesan, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7550751/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Mar, 2026 Read the published version in Journal of Human Hypertension → Version 1 posted 9 You are reading this latest preprint version Abstract Resistant Hypertension is blood pressure control requiring more than three drugs – commonly a thiazide like diuretic, calcium channel blocker (CCB), and RAAS inhibitor. But, in clinical practice, several patients take more than three drugs for hypertension (HTN) control that may not contain all these three drugs. There is no dedicated real-world large-scale study in this segment. A prospective multicentric cross-sectional observational study among Cardiologists on the prescription pattern in adults (aged ≥ 18 years) on more than three drugs for the control of (HTN) was undertaken. The drugs could be from any class of the antihypertensive medication. Persons with renal denervation, renal transplant and known renal artery stenosis were excluded. From 10 centers, 420 patients were studied. The mean age was 65.2 years (M: F ratio 1: 0.8). RAASi, CCB and diuretic use were 89%, 85%, and 82% respectively. Betablocker (BB) use was very high at 85%. The use of MRAs was only 39% while this was the recommended fourth drug. Even among patients who qualify for the diagnosis of resistant HTN on CCB, RAASi, and thiazide like diuretic (n=273), when the serum Potassium was ≤ 4.5 mEq/L, the MRA use was only 38%. This is the largest real-world multicenter observational study and has shown that the prescription pattern of more than three drugs for the control of HTN among cardiologists shows an overwhelming use of BB (85%) and gross underutilization of MRAs (39%) – highlighting the scope for improvement in the prescription pattern during polypharmacy of HTN. Health sciences/Diseases/Cardiovascular diseases/Hypertension Health sciences/Diseases/Cardiovascular diseases/Vascular diseases Figures Figure 1 Summary Table What is known about the topic? • Smaller real-world studies (n < 75) on more than three drugs for the control of hypertension have limited data on the use of mineralocorticoid receptor antagonist (MRA). What this study adds • The present large scale multicentric study of this cohort of patients (n=420) showed that cardiologist use of ARBs, CCBs and diuretics were 88%, 85% and 82% respectively. • The betablockers were prescribed in 85% of patients with gross underutilization of MRAs(39%). • Among patients who qualify for the diagnosis of resistant HTN on CCB, RAASi, and thiazide like diuretic (n=273), when the serum Potassium was = 4.5 mEq/L, the MRA use was only 38%. • The present study emphasizes the scope for improvement in the guideline directed use of MRAs. Introduction The fifth National Family Health survey (NFHS-V) found that the prevalence of systemic hypertension (HTN) was 22.6% in India. The prevalence of HTN in the urban and rural population were 25% and 21.4% respectively (1). The control rate of hypertension ranged between 10 and 25%. Most of the major HTN trials required more than two drugs for the control of hypertension. Resistant HTN is defined as failure to achieve a blood pressure (BP) of < 140/90 mm Hg despite the use of maximal or maximally tolerated doses of a renin angiotensin system (RAS) blocker, a calcium channel blocker (CCB) and a diuretic (thiazide or thiazide like). The overall prevalence of resistant Hypertension is 10-20%. Following the three drugs, the fourth drug is usually a mineralocorticoid receptor antagonist (MRA) when the serum potassium is < 4.5 mEq/L(2). However, in real world practice, this is seldom followed, and in general, the use of betablockers has been very high among Indians, since the resting heart rate among Indians is higher(3). A study of the prescription pattern of antihypertensive medication among 395 patients did not record a single patient on MRA(4). Another study on diabetic subjects had similar findings (5). There is no large study on the pattern of antihypertensive drug use among cardiologists in real world with unrestricted use of medication. The present study was conducted to identify the prescription pattern of more than three drugs for the control of HTN among cardiologists. The classical definition of resistant hypertension was not used, since we felt that this will broaden our understanding of the use of antihypertensive medication, especially the early use of betablockers and utilization of MRAs when four or more drugs are used. Methodology The study design was a prospective, multicentric cross-sectional observational study at outpatient cardiology facilities. Consecutive hypertensive adult patients aged more than 18 years on more than three antihypertensive drugs were included. Patients with post renal denervation status, post renal transplantation, renal artery stenosis and incomplete data were excluded. Ethics Committee approval was secured from two institutions. An informed consent was obtained from all enrolled patients. Comorbidities were captured. Office blood pressure and pulse rate were recorded. The details of all the medication including dose were recorded. Since this was a cross-sectional study, no follow up was planned. The data was collected and tabulated in Microsoft Excel and analyzed by a statistician using SPSS software. After discerning the overall pattern of drug usage, the use of MRAs was corroborated with serum potassium levels with a cutoff value ≤ 4.5 mEq/L in the overall group and specifically in those patients who were on RAASi, CCB and diuretics (fitting into the diagnosis of Resistant Hypertension). The association between serum potassium levels (cutoff of ≤ 4.5 mEq/L ) and MRA (Mineralocorticoid Receptor Antagonist) prescription was assessed using the Chi-square test. The binary logistic regression model included the variables Age, Sex (Male), Duration of Hypertension, Diabetes Mellitus (DM), Left Ventricular Hypertrophy (LVH), Serum Creatinine, and Serum Potassium (categorized as cutoff at 4.5). The dependent variable was whether MRA was prescribed or not. Results Ten outpatient cardiology centers were selected and patients enrolled. Out of 427 patients whose data were available, 7 were excluded due to incomplete data and 420 patients were used for final analysis. The mean age was 65.2 years with a male: female ratio of 1: 0.8. The duration of HTN was 14.26 +/- 8.26 years. The overall demographic and clinical parameters are given in table 1. The Mean Recorded BP was 143/79 +/- 17/13 mm Hg. Type 2 diabetes mellitus was present in 270(64%) while 190 (45%) had underlying ischemic heart disease. History of snoring or known obstructive sleep apnea was noted in 65 persons (15%). Left ventricular hypertrophy was recorded by echocardiography in 321 out of 407 persons with a recorded echocardiogram (79%). Regular physical activity, and salt restriction at 319(76%), and 366(87%) respectively were noted. Majority of the patients 282(67%) were on home blood pressure monitoring. The pattern of drug use is summarized in table 2. And the graphical representation is given in Fig. 1. Among the drugs defined as the first three, the most used drug was an angiotensin receptor blocker (ARB) at 88% followed by CCB and diuretic at 85% and 82% respectively. Betablocker use was a very high 85%. The proverbial fourth drug, the MRA was prescribed in only 39% of patients. Hydralazine and extended-release prazosin were prescribed at 25% each. The other drugs used were moxonidine (9%), clonidine (2%), minoxidil (1%) and angiotensin converting enzyme inhibitor (1%). MRA analysis The association between serum potassium levels (with cutoff of 4.5mEq/L) and MRA (Mineralocorticoid Receptor Antagonist) prescription was assessed using the Chi-square test. A serum potassium estimation was available in 347 patients. Among patients who were prescribed MRA, 76.2% (n = 115) had serum potassium levels ≤ 4.5 mEq/L, while 23.8% (n = 36) had potassium levels > 4.5 mEq/L. In contrast, among those not prescribed MRA, 63.3% (n = 124) had serum potassium levels ≤ 4.5 mEq/L and 36.7% (n = 72) had levels > 4.5 mEq/L. Overall, 68.9% of the entire sample had potassium levels ≤ 4.5. The Pearson Chi-square test showed a statistically significant association between serum potassium levels and MRA prescription ( χ² = 6.614, df = 1, p = 0.010 ). This indicates that individuals with lower serum potassium (≤ 4.5) were significantly more likely to be prescribed an MRA compared to those with higher potassium levels. The binary logistic regression model included the variables Age, Sex (Male), Duration of Hypertension, Diabetes Mellitus (DM), Left Ventricular Hypertrophy (LVH), Serum Creatinine, and Serum Potassium (categorized as cutoff at 4.5 mEq/L). The dependent variable was whether MRA was prescribed or not. Among the aforementioned variables studied, only Serum Potassium ≤ 4.5 mEq/L was found to be a statistically significant predictor of MRA prescription. The results are given in table 3. Other demographic and clinical variables did not independently predict MRA use in this model. Out of the total 420 persons, 273(65%) were on all three drugs (RAASi + CCB + Diuretic) to qualify for resistant HTN. MRA use in this subset was 27% (75 out of 273 persons). Seventy persons had a recent ( 4.5 mEq/L it was 18%. Discussion Multiple drugs are required for the control of HTN. Data and rationale on the use of antihypertensive medication among cardiologists in real-world has not been studied. The present study is the largest available real-world data on the prescription pattern of more than three drugs for the control of HTN. ARBs are the preferred drug (88%) while only 1% were on ACEI. The only speculative explanation is that cardiologists perceive ARBs to be better at lowering BP– this will need a separate survey among the participating cardiologists, which is planned based on the results. Dhanraj et al studied polypharmacy in HTN of whom 37 persons were on ≥ 4 drugs. ARB use was 97%, while the use of CCB (92%), diuretic (81%), ACEI (78%) and BB (65%) were also high. With 97% on ARBs and 78% on ACEI, several patients were on combined ACEI and ARBs( 5 ). This study was published in 2012, much later than the ONTARGET trial (published in 2008) which highlighted the harmful effects of combining ACEI and ARBs( 6 ). A study on the pattern of hypertensive drug use in a tertiary care hospital in India (n = 200) had only 19 persons on four drugs. All the persons were on a combination of ARB, CCB, Diuretic and BB( 4 ). Binary logistic regression analysis of Age, Sex (Male), Duration of Hypertension, Diabetes Mellitus (DM), Left Ventricular Hypertrophy (LVH), Serum Creatinine, and Serum Potassium (categorized as cutoff at 4.5 mEq/L), reiterated the recommendation of using MRA when serum potassium levels are ≤ 4.5 mEq/L ( 2 ). Among the subset of patients who qualified for the definition of resistant HTN(n = 273), 27% were on MRAs. When serum potassium was ≤ 4.5 mEq/L, only 38% were on MRAs, implying that the MRA use among cardiologists was not strictly governed by serum potassium levels. The two studies from India do not even mention the use of MRAs( 4 ). Literature search on the real-world prescription pattern in HTN showed five studies with some patients on more than three drugs for the control of HTN. The present study was the largest and the comparative details are given in Table 4. Betablocker use among cardiologists was very high at 85%. Previous studies in India have shown that the resting heart rate is higher and this could be a possible explanation for the high use of BB. In Narkar et al data 47% were on BB, and in Dhanaraj et al data 64% were on BB( 4 , 5 ). Comparing the global data on the real world polypharmacy in HTN, the present study is the largest single cohort of patients on more than three drugs for the control of HTN. This highlights some important facts. (i) The use of the conventional first line three drugs namely the RAASi, CCBs and diuretics is high at 89%, 85% and 82% respectively. (ii) the Use of BB is 85% which is also high and could possibly highlight the fact that the basal heart rate in Indians is higher. (iii) Overall MRA use is low at 39% and even when the serum potassium levels are ≤ 4.5 mEq/L - underlining the underutilization of MRAs. But still, only serum Potassium ≤ 4.5 mEq/L was the only significant correlate to the prescription of MRAs. The present real-world observational data highlights that the optimal management of HTN has a significant scope for improvement among cardiologists with significant underutilization of MRAs despite indications. Limitations of the study are (i) cross sectional study and not longitudinal to assess the response (ii) compliance of drugs is not confirmed (iii) serum potassium was not done in all the patients (although this is a real-world study) (iv) BP control was not assessed to look at the response (this was not the aim of the study) To conclude, when more than three drugs were used to control HTN, cardiologists used BB (85%) while MRA use was just 39%. Serum potassium < 4.5 mEq/L was the only statistically significant predictor for the use of MRAs despite its gross underutilization. Future guidance with a follow-up among the same group of investigators would determine if the message of underutilization of MRAs has reflected in clinical practice. Physician education on the awareness of the use of MRAs is the need of the hour. Declarations Conflict of Interest Statement All the authors do not have any conflict of interest with the present study. There is no industry sponsorship for the study. Acknowledgements Associates for Cardiology Education and Research in Tamilnadu is a group of cardiologists who are involved in research in Cardiology in Tamilnadu, a state in India. References Mohammad R, Bansod DW. Hypertension in India: a gender-based study of prevalence and associated risk factors. BMC Public Health. 2024;24(1):2681. Overview | Hypertension in adults: diagnosis and management | Guidance | NICE [Internet]. NICE; 2019 [cited 2023 Dec 5]. Available from: https://www.nice.org.uk/guidance/ng136 Kaul U, Bhagwat A, Omboni S, Pancholia AK, Hardas S, Bardoloi N, et al. Blood pressure and heart rate related to sex in untreated subjects: the India ABPM study. J Clin Hypertens (Greenwich). 2020;22(7):1154–62. Narkar NS, Deshpande T, Rane BT, Kothari R, Tilak AV, Bhide H. Pattern of Antihypertensive Drugs Prescribed in a Tertiary Care Hospital in Western India. Biomedical and Pharmacology Journal. 2021;14(2):961–9. Dhanaraj E, Raval A, Yadav R, Bhansali A, Tiwari P. Prescription Pattern of Antihypertensive Agents in T2DM Patients Visiting Tertiary Care Centre in North India. International Journal of Hypertension. 2012;2012:e520915. ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547–59. 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. Journal of Research in Pharmacy Practice. 2019;8(2):92. Shastry R, Adhikari MRP, Ullal SD, Kotian S. Usage of diuretics among diabetic-hypertensive patients. Asian Journal of Medical Sciences. 2015;6(2):14–7. Tandon VR, Sharma S, Mahajan S, Mahajan A, Khajuria V, Mahajan V, et al. Antihypertensive drug prescription patterns, rationality, and adherence to Joint National Committee-7 hypertension treatment guidelines among Indian postmenopausal women. Journal of Mid-life Health. 2014;5(2):78. Bulatova NR, Yousef AM, AbuRuz SD, Farha RA. Hypertension Management and Factors Associated with Blood Pressure Control in Jordanian Patients Attending Cardiology Clinic. Tropical Journal of Pharmaceutical Research. 2013;12(5):827–33. Tables Tables 1 to 4 are available in the Supplementary Files section. Additional Declarations There is NO conflict of interest to disclose. Supplementary Files Table1.Demographicandclinicaldataofthestudy.xlsx Table 1 Table2Patternofdrugusewhenmorethanthreedrugsareusedforthecontrolofhypertension.xlsx Table 2 Table3ResultsofthebinarylogisticregressionmodelwithprescriptionofMRAasthedependentvariable.xlsx Table 3 Table4Prescriptionpatternwhenfourormoredrugswereusedtotreatsystemichypertension.xlsx Table 4 Cite Share Download PDF Status: Published Journal Publication published 17 Mar, 2026 Read the published version in Journal of Human Hypertension → Version 1 posted Editorial decision: revise 09 Jan, 2026 Review # 2 received at journal 17 Oct, 2025 Reviewer # 2 agreed at journal 16 Oct, 2025 Reviewer # 1 agreed at journal 25 Sep, 2025 Reviewers invited by journal 20 Sep, 2025 Editor assigned by journal 18 Sep, 2025 Submission checks completed at journal 10 Sep, 2025 First submitted to journal 09 Sep, 2025 Unknown event 09 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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01:06:24","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10904,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1\u003c/p\u003e","description":"","filename":"Table1.Demographicandclinicaldataofthestudy.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7550751/v1/afb289020946ddbf29bacf49.xlsx"},{"id":92680688,"identity":"be432971-31a9-47b7-acc2-239a24ca570d","added_by":"auto","created_at":"2025-10-03 01:06:24","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":9681,"visible":true,"origin":"","legend":"\u003cp\u003eTable 2\u003c/p\u003e","description":"","filename":"Table2Patternofdrugusewhenmorethanthreedrugsareusedforthecontrolofhypertension.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7550751/v1/818cc815e895f5d6471083c7.xlsx"},{"id":92680696,"identity":"94ab239d-d52e-4f23-b1a1-46473f25eff3","added_by":"auto","created_at":"2025-10-03 01:06:25","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":9883,"visible":true,"origin":"","legend":"Table 3","description":"","filename":"Table3ResultsofthebinarylogisticregressionmodelwithprescriptionofMRAasthedependentvariable.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7550751/v1/90be2bd0adc6e6189f190d42.xlsx"},{"id":92680690,"identity":"23e8ece2-ccc1-493c-ac06-e053acbddf59","added_by":"auto","created_at":"2025-10-03 01:06:24","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":10029,"visible":true,"origin":"","legend":"Table 4","description":"","filename":"Table4Prescriptionpatternwhenfourormoredrugswereusedtotreatsystemichypertension.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7550751/v1/fac65adf19f6a46f31388425.xlsx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"A Multi-Centric Study of Real-World Prescription Pattern of More Than Three Drugs for the Control of Hypertension Among Cardiologists","fulltext":[{"header":"Summary Table","content":"\u003cp\u003eWhat is known about the topic?\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;Smaller real-world studies (n \u0026lt; \u0026nbsp;75) on more than three drugs for the control of hypertension have limited data on the use of mineralocorticoid receptor antagonist (MRA).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhat this study adds\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;The present large scale multicentric study of this cohort of patients (n=420) showed that cardiologist use of ARBs, CCBs and diuretics were 88%, 85% and 82% respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;The betablockers were prescribed in 85% of patients with gross underutilization of MRAs(39%).\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;Among patients who qualify for the diagnosis of resistant HTN on CCB, RAASi, and thiazide like diuretic (n=273), when the serum Potassium was = 4.5 mEq/L, the MRA use was only 38%.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;The present study emphasizes the scope for improvement in the guideline directed use of MRAs.\u0026nbsp;\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eThe fifth National Family Health survey (NFHS-V) found that the prevalence of systemic hypertension (HTN) was 22.6% in India. The prevalence of HTN in the urban and rural population were 25% and 21.4% respectively (1). The control rate of hypertension ranged between 10 and 25%. Most of the major HTN trials required more than two drugs for the control of hypertension.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResistant HTN is defined as failure to achieve a blood pressure (BP) of \u0026lt; 140/90 mm Hg despite the use of maximal or maximally tolerated doses of a renin angiotensin system (RAS) blocker, a calcium channel blocker (CCB) and a diuretic (thiazide or thiazide like). The overall prevalence of resistant Hypertension is 10-20%. Following the three drugs, the fourth drug is usually a mineralocorticoid receptor antagonist (MRA) when the serum potassium is \u0026lt; 4.5 mEq/L(2). \u0026nbsp;However, in real world practice, this is seldom followed, and in general, the use of betablockers has been very high among Indians, since the resting heart rate among Indians is higher(3). A study of the prescription pattern of antihypertensive medication among 395 patients did not record a single patient on MRA(4). \u0026nbsp;Another study on diabetic subjects had similar findings (5). There is no large study on the pattern of antihypertensive drug use among cardiologists in real world with unrestricted use of medication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe present study was conducted to identify the prescription pattern of more than three drugs for the control of HTN among cardiologists. The classical definition of resistant hypertension was not used, since we felt that this will broaden our understanding of the use of antihypertensive medication, especially the early use of betablockers and utilization of MRAs when four or more drugs are used.\u0026nbsp;\u003c/p\u003e"},{"header":"Methodology","content":"\u003cp\u003eThe study design was a prospective, multicentric cross-sectional observational study at outpatient cardiology facilities. Consecutive hypertensive adult patients aged more than 18 years on more than three antihypertensive drugs were included. Patients with post renal denervation status, post renal transplantation, renal artery stenosis and incomplete data were excluded. Ethics Committee approval was secured from two institutions. An informed consent was obtained from all enrolled patients. Comorbidities were captured. Office blood pressure and pulse rate were recorded. The details of all the medication including dose were recorded. Since this was a cross-sectional study, no follow up was planned. The data was collected and tabulated in Microsoft Excel and analyzed by a statistician using SPSS software.\u003c/p\u003e\u003cp\u003eAfter discerning the overall pattern of drug usage, the use of MRAs was corroborated with serum potassium levels with a cutoff value\u0026thinsp;\u0026le;\u0026thinsp;4.5 mEq/L in the overall group and specifically in those patients who were on RAASi, CCB and diuretics (fitting into the diagnosis of Resistant Hypertension). The association between serum potassium levels (cutoff of \u0026le;\u0026thinsp;4.5 mEq/L ) and MRA (Mineralocorticoid Receptor Antagonist) prescription was assessed using the Chi-square test. The binary logistic regression model included the variables Age, Sex (Male), Duration of Hypertension, Diabetes Mellitus (DM), Left Ventricular Hypertrophy (LVH), Serum Creatinine, and Serum Potassium (categorized as cutoff at 4.5). The dependent variable was whether MRA was prescribed or not.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eTen outpatient cardiology centers were selected and patients enrolled. Out of 427 patients whose data were available, 7 were excluded due to incomplete data and 420 patients were used for final analysis. The mean age was 65.2 years with a male: female ratio of 1: 0.8. The duration of HTN was 14.26 +/- 8.26 years. The overall demographic and clinical parameters are given in table 1.\u003c/p\u003e\u003cp\u003eThe Mean Recorded BP was 143/79 +/- 17/13 mm Hg. Type 2 diabetes mellitus was present in 270(64%) while 190 (45%) had underlying ischemic heart disease. History of snoring or known obstructive sleep apnea was noted in 65 persons (15%). Left ventricular hypertrophy was recorded by echocardiography in 321 out of 407 persons with a recorded echocardiogram (79%). Regular physical activity, and salt restriction at 319(76%), and 366(87%) respectively were noted. Majority of the patients 282(67%) were on home blood pressure monitoring.\u003c/p\u003e\u003cp\u003eThe pattern of drug use is summarized in table 2. And the graphical representation is given in Fig.\u0026nbsp;1.\u003c/p\u003e\u003cp\u003eAmong the drugs defined as the first three, the most used drug was an angiotensin receptor blocker (ARB) at 88% followed by CCB and diuretic at 85% and 82% respectively. Betablocker use was a very high 85%. The proverbial fourth drug, the MRA was prescribed in only 39% of patients. Hydralazine and extended-release prazosin were prescribed at 25% each. The other drugs used were moxonidine (9%), clonidine (2%), minoxidil (1%) and angiotensin converting enzyme inhibitor (1%).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eMRA analysis\u003c/h2\u003e\u003cp\u003eThe association between serum potassium levels (with cutoff of 4.5mEq/L) and MRA (Mineralocorticoid Receptor Antagonist) prescription was assessed using the Chi-square test. A serum potassium estimation was available in 347 patients. Among patients who were prescribed MRA, 76.2% (n\u0026thinsp;=\u0026thinsp;115) had serum potassium levels\u0026thinsp;\u0026le;\u0026thinsp;4.5 mEq/L, while 23.8% (n\u0026thinsp;=\u0026thinsp;36) had potassium levels\u0026thinsp;\u0026gt;\u0026thinsp;4.5 mEq/L. In contrast, among those not prescribed MRA, 63.3% (n\u0026thinsp;=\u0026thinsp;124) had serum potassium levels\u0026thinsp;\u0026le;\u0026thinsp;4.5 mEq/L and 36.7% (n\u0026thinsp;=\u0026thinsp;72) had levels\u0026thinsp;\u0026gt;\u0026thinsp;4.5 mEq/L. Overall, 68.9% of the entire sample had potassium levels\u0026thinsp;\u0026le;\u0026thinsp;4.5. The Pearson Chi-square test showed a statistically significant association between serum potassium levels and MRA prescription \u003cb\u003e(\u003c/b\u003eχ\u0026sup2; = 6.614, df\u0026thinsp;=\u0026thinsp;1, p\u0026thinsp;=\u0026thinsp;0.010\u003cb\u003e).\u003c/b\u003e This indicates that individuals with lower serum potassium (\u0026le;\u0026thinsp;4.5) were significantly more likely to be prescribed an MRA compared to those with higher potassium levels.\u003c/p\u003e\u003cp\u003eThe binary logistic regression model included the variables Age, Sex (Male), Duration of Hypertension, Diabetes Mellitus (DM), Left Ventricular Hypertrophy (LVH), Serum Creatinine, and Serum Potassium (categorized as cutoff at 4.5 mEq/L). The dependent variable was whether MRA was prescribed or not. Among the aforementioned variables studied, only Serum Potassium\u0026thinsp;\u0026le;\u0026thinsp;4.5 mEq/L was found to be a statistically significant predictor of MRA prescription. The results are given in table 3. Other demographic and clinical variables did not independently predict MRA use in this model.\u003c/p\u003e\u003cp\u003eOut of the total 420 persons, 273(65%) were on all three drugs (RAASi\u0026thinsp;+\u0026thinsp;CCB\u0026thinsp;+\u0026thinsp;Diuretic) to qualify for resistant HTN. MRA use in this subset was 27% (75 out of 273 persons). Seventy persons had a recent (\u0026lt;\u0026thinsp;1 month) serum potassium recorded. When serum potassium was \u0026le;\u0026thinsp;4.5 mEq/L, 38% were on MRAs and when serum potassium was \u0026gt;\u0026thinsp;4.5 mEq/L it was 18%.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eMultiple drugs are required for the control of HTN. Data and rationale on the use of antihypertensive medication among cardiologists in real-world has not been studied. The present study is the largest available real-world data on the prescription pattern of more than three drugs for the control of HTN.\u003c/p\u003e\u003cp\u003eARBs are the preferred drug (88%) while only 1% were on ACEI. The only speculative explanation is that cardiologists perceive ARBs to be better at lowering BP\u0026ndash; this will need a separate survey among the participating cardiologists, which is planned based on the results. Dhanraj et al studied polypharmacy in HTN of whom 37 persons were on \u0026ge;\u0026thinsp;4 drugs. ARB use was 97%, while the use of CCB (92%), diuretic (81%), ACEI (78%) and BB (65%) were also high. With 97% on ARBs and 78% on ACEI, several patients were on combined ACEI and ARBs(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). This study was published in 2012, much later than the ONTARGET trial (published in 2008) which highlighted the harmful effects of combining ACEI and ARBs(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). A study on the pattern of hypertensive drug use in a tertiary care hospital in India (n\u0026thinsp;=\u0026thinsp;200) had only 19 persons on four drugs. All the persons were on a combination of ARB, CCB, Diuretic and BB(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eBinary logistic regression analysis of Age, Sex (Male), Duration of Hypertension, Diabetes Mellitus (DM), Left Ventricular Hypertrophy (LVH), Serum Creatinine, and Serum Potassium (categorized as cutoff at 4.5 mEq/L), reiterated the recommendation of using MRA when serum potassium levels are \u0026le;\u0026thinsp;4.5 mEq/L (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAmong the subset of patients who qualified for the definition of resistant HTN(n\u0026thinsp;=\u0026thinsp;273), 27% were on MRAs. When serum potassium was \u0026le;\u0026thinsp;4.5 mEq/L, only 38% were on MRAs, implying that the MRA use among cardiologists was not strictly governed by serum potassium levels. The two studies from India do not even mention the use of MRAs(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Literature search on the real-world prescription pattern in HTN showed five studies with some patients on more than three drugs for the control of HTN. The present study was the largest and the comparative details are given in Table\u0026nbsp;4.\u003c/p\u003e\u003cp\u003eBetablocker use among cardiologists was very high at 85%. Previous studies in India have shown that the resting heart rate is higher and this could be a possible explanation for the high use of BB. In Narkar et al data 47% were on BB, and in Dhanaraj et al data 64% were on BB(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eComparing the global data on the real world polypharmacy in HTN, the present study is the largest single cohort of patients on more than three drugs for the control of HTN. This highlights some important facts. (i) The use of the conventional first line three drugs namely the RAASi, CCBs and diuretics is high at 89%, 85% and 82% respectively. (ii) the Use of BB is 85% which is also high and could possibly highlight the fact that the basal heart rate in Indians is higher. (iii) Overall MRA use is low at 39% and even when the serum potassium levels are \u0026le;\u0026thinsp;4.5 mEq/L - underlining the underutilization of MRAs. But still, only serum Potassium\u0026thinsp;\u0026le;\u0026thinsp;4.5 mEq/L was the only significant correlate to the prescription of MRAs.\u003c/p\u003e\u003cp\u003eThe present real-world observational data highlights that the optimal management of HTN has a significant scope for improvement among cardiologists with significant underutilization of MRAs despite indications.\u003c/p\u003e\u003cp\u003eLimitations of the study are (i) cross sectional study and not longitudinal to assess the response (ii) compliance of drugs is not confirmed (iii) serum potassium was not done in all the patients (although this is a real-world study) (iv) BP control was not assessed to look at the response (this was not the aim of the study)\u003c/p\u003e\u003cp\u003eTo conclude, when more than three drugs were used to control HTN, cardiologists used BB (85%) while MRA use was just 39%. Serum potassium\u0026thinsp;\u0026lt;\u0026thinsp;4.5 mEq/L was the only statistically significant predictor for the use of MRAs despite its gross underutilization.\u003c/p\u003e\u003cp\u003eFuture guidance with a follow-up among the same group of investigators would determine if the message of underutilization of MRAs has reflected in clinical practice. Physician education on the awareness of the use of MRAs is the need of the hour.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflict of Interest Statement\u003c/h2\u003e\u003cp\u003eAll the authors do not have any conflict of interest with the present study. There is no industry sponsorship for the study.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eAssociates for Cardiology Education and Research in Tamilnadu is a group of cardiologists who are involved in research in Cardiology in Tamilnadu, a state in India.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMohammad R, Bansod DW. Hypertension in India: a gender-based study of prevalence and associated risk factors. BMC Public Health. 2024;24(1):2681.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOverview | Hypertension in adults: diagnosis and management | Guidance | NICE [Internet]. NICE; 2019 [cited 2023 Dec 5]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.nice.org.uk/guidance/ng136\u003c/span\u003e\u003cspan address=\"https://www.nice.org.uk/guidance/ng136\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKaul U, Bhagwat A, Omboni S, Pancholia AK, Hardas S, Bardoloi N, et al. Blood pressure and heart rate related to sex in untreated subjects: the India ABPM study. J Clin Hypertens (Greenwich). 2020;22(7):1154\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNarkar NS, Deshpande T, Rane BT, Kothari R, Tilak AV, Bhide H. Pattern of Antihypertensive Drugs Prescribed in a Tertiary Care Hospital in Western India. Biomedical and Pharmacology Journal. 2021;14(2):961\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDhanaraj E, Raval A, Yadav R, Bhansali A, Tiwari P. Prescription Pattern of Antihypertensive Agents in T2DM Patients Visiting Tertiary Care Centre in North India. International Journal of Hypertension. 2012;2012:e520915.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlkaabi MS, Rabbani SA, Rao PGM, Ali SR. Prescription Pattern of Antihypertensive Drugs: An Experience from a Secondary Care Hospital in the United Arab Emirates. Journal of Research in Pharmacy Practice. 2019;8(2):92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShastry R, Adhikari MRP, Ullal SD, Kotian S. Usage of diuretics among diabetic-hypertensive patients. Asian Journal of Medical Sciences. 2015;6(2):14\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTandon VR, Sharma S, Mahajan S, Mahajan A, Khajuria V, Mahajan V, et al. Antihypertensive drug prescription patterns, rationality, and adherence to Joint National Committee-7 hypertension treatment guidelines among Indian postmenopausal women. Journal of Mid-life Health. 2014;5(2):78.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBulatova NR, Yousef AM, AbuRuz SD, Farha RA. Hypertension Management and Factors Associated with Blood Pressure Control in Jordanian Patients Attending Cardiology Clinic. Tropical Journal of Pharmaceutical Research. 2013;12(5):827\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-human-hypertension","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jhh","sideBox":"Learn more about [Journal of Human Hypertension](http://www.nature.com/jhh/)","snPcode":"41371","submissionUrl":"https://mts-jhh.nature.com/cgi-bin/main.plex","title":"Journal of Human Hypertension","twitterHandle":"@jhhypertension","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7550751/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7550751/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eResistant Hypertension is blood pressure control requiring more than three drugs – commonly a thiazide like diuretic, calcium channel blocker (CCB), and RAAS inhibitor. But, in clinical practice, several patients take more than three drugs for hypertension (HTN) control that may not contain all these three drugs. There is no dedicated real-world large-scale study in this segment. A prospective multicentric cross-sectional observational study among Cardiologists on the prescription pattern in adults (aged ≥ 18 years) on more than three drugs for the control of (HTN) was undertaken. The drugs could be from any class of the antihypertensive medication. Persons with renal denervation, renal transplant and known renal artery stenosis were excluded. From 10 centers, 420 patients were studied. The mean age was 65.2 years (M: F ratio 1: 0.8). RAASi, CCB and diuretic use were 89%, 85%, and 82% respectively. Betablocker (BB) use was very high at 85%. The use of MRAs was only 39% while this was the recommended fourth drug. Even among patients who qualify for the diagnosis of resistant HTN on CCB, RAASi, and thiazide like diuretic (n=273), when the serum Potassium was ≤ 4.5 mEq/L, the MRA use was only 38%. This is the largest real-world multicenter observational study and has shown that the prescription pattern of more than three drugs for the control of HTN among cardiologists shows an overwhelming use of BB (85%) and gross underutilization of MRAs (39%) – highlighting the scope for improvement in the prescription pattern during polypharmacy of HTN.\u003c/p\u003e","manuscriptTitle":"A Multi-Centric Study of Real-World Prescription Pattern of More Than Three Drugs for the Control of Hypertension Among Cardiologists","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-03 01:06:20","doi":"10.21203/rs.3.rs-7550751/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2026-01-09T17:55:56+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-10-17T08:41:59+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-10-16T11:32:41+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-09-25T07:32:49+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-09-20T20:43:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-19T02:17:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-10T18:21:29+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Human Hypertension","date":"2025-09-09T15:25:37+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2025-09-09T11:28:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-human-hypertension","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jhh","sideBox":"Learn more about [Journal of Human Hypertension](http://www.nature.com/jhh/)","snPcode":"41371","submissionUrl":"https://mts-jhh.nature.com/cgi-bin/main.plex","title":"Journal of Human Hypertension","twitterHandle":"@jhhypertension","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c6414399-3d45-4b5b-8b5f-725d894804b0","owner":[],"postedDate":"October 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":55061493,"name":"Health sciences/Diseases/Cardiovascular diseases/Hypertension"},{"id":55061494,"name":"Health sciences/Diseases/Cardiovascular diseases/Vascular diseases"}],"tags":[],"updatedAt":"2026-03-18T07:12:29+00:00","versionOfRecord":{"articleIdentity":"rs-7550751","link":"https://doi.org/10.1038/s41371-026-01128-7","journal":{"identity":"journal-of-human-hypertension","isVorOnly":false,"title":"Journal of Human Hypertension"},"publishedOn":"2026-03-17 04:00:00","publishedOnDateReadable":"March 17th, 2026"},"versionCreatedAt":"2025-10-03 01:06:20","video":"","vorDoi":"10.1038/s41371-026-01128-7","vorDoiUrl":"https://doi.org/10.1038/s41371-026-01128-7","workflowStages":[]},"version":"v1","identity":"rs-7550751","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7550751","identity":"rs-7550751","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}