Analyzing Resistant hypertension: An insight into its etiology, prevalence, risk factors and management

Published On 2021-09-22 05:46 GMT   |   Update On 2021-10-07 06:55 GMT

Managing hypertension has been a major health concern among physicians, with its ever-increasing incidence, risk factors, and related co-morbidities. With India facing a striking prevalence of hypertensives, as high as 29.8%, a relatively lesser-studied health condition known as Resistant Hypertension (RH) has been raising concerns in the last decade. Data suggests that 12 - 15% of hypertensive patients develop Resistant Hypertension, in due course(1). RH has an established association with cardiovascular diseases like myocardial infarction, congestive heart failure, coronary heart disease, and stroke; pulmonary artery disease, renal failures, and all-cause mortality (2). Owing to its limited response to conventional antihypertensive therapy, Resistant hypertension is now being acknowledged as a distinct disease entity(3). With studies confirming that an optimum BP control reduced the risk of incident stroke, coronary heart disease, or heart failure significantly among those with RH (4), an elaborate knowledge on the disease and its management is the need of the hour.


What is Resistant Hypertension?

According to the American Heart Association(AHA), Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes, commonly including a long-acting calcium channel blocker, a blocker of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic, even after being administered at maximum or maximally tolerated daily doses and the appropriate dosing frequency. RH also includes patients whose BP achieves target values on ≥4 antihypertensive medications. (3) Resonating with the above definition provided by AHA, other contemporary guidelines on hypertension all mandate that the BP remains uncontrolled on at least 3 antihypertensive agents including a diuretic to qualify as RH. (5) Despite such a well-defined interpretation of this high-risk disease, RH has been inconsistently reported in clinical practice, due to inappropriate diagnostic protocols, limited knowledge on contributing factors, coupled with patient unawareness. (6)


Incorrect techniques of BP measurement, out-of-office BP, and self-monitored BP can have a false positive or negative influence on BP results and can lead to misdiagnosis of resistant hypertension, making Ambulatory BP monitoring (ABPM) the standard for diagnosing RH. (7,8)Other factors like the "white-coat effect", nonadherence or suboptimal adherence to prescribed antihypertensive medications are among the most noted patient-related factors that obscure a proper diagnosis of RH.(3)


Being multifactorial in etiology, the exact underlying mechanism of RH remains to be fully deciphered. Managing RH has been a challenge for physicians with a simultaneous focus towards confirming true treatment resistance; identification of causes contributing to treatment resistance, including secondary causes of hypertension; and documentation of target-organ damage. Obtaining a balance of lifestyle modifications and dietary intake, while formulating an optimized pharmacotherapy forms the cornerstone of successfully managing RH.(9)


Prevalence-With a variable prevalence ranging from 12% to 15% (4) in population-based and 15% to 18% (10) of clinic-based reports, the increasing interest in RH has been mirrored in the almost four-fold rise of yearly publications on RH, over the past decade. (11)

In a one of its kind study, by Rajkumar Bharatia et al, aimed at determining the number of patients with resistant hypertension across India, researchers observed a prevalence rate of 19.5%, documenting 80% of the RH patients to be aged between 46-65 years. (12)According to reports from a large population-based study, patients with RH had a 32% increased risk of developing end-stage renal disease, a 24% increased risk of an ischemic heart event, a 46% increased risk of heart failure, a 14% increased risk of stroke, and a 6% increased risk of death. (13)

Identifying the risk factors/comorbidities associated with RH- Among the multiple risk factors associated with RH, age (>55 Years) obesity, diabetics, black ethnicity, high baseline blood pressure, and female gender have been most stressed upon.(14,15)

Studies worldwide have established that higher dietary sodium intake, chronic alcoholism, reduced physical activity, medications like certain NSAIDs, oral contraceptives and hormone replacement pills, immunosuppressive agents, conditions like obstructive sleep apnea are key factors (16,3) that contribute to Resistant Hypertension.

Treating RH with the triple-drug combination

The way ahead - In its updated 2018 Guideline (3), the American Heart Association recommends a triple-drug combination of Angiotensin-converting enzyme Inhibitor (ACEi) or Angiotensin receptor blockers (ARB) + Calcium Channel Blockers (CCB) + Diuretic (or loop diuretic)as the first line of treatment in resistant hypertension, further specifying that these 3 separate pharmacological classes of antihypertensive agents must be given at maximally tolerated doses. The guidelines also highlight that among diuretics, chlorthalidone induces natriuresis in cases with eGFR > 30 mL/min/1.73 m2 ; however in hypoalbuminemia states i.e., serum albumin < 30 mL/min/1.73 m2, a long-acting loop diuretic such as torsemide should be advocated.

Choice of ARB-

• 24-hour ABPM studies demonstrate that azilsartan medoximil provides on average an additional 4 to 8 mm Hg further SBP reduction over other ARBs (eg, valsartan and olmesartan) or the ACE inhibitor ramipril.(17,18)

• A study by Pradhan et al concluded that among all ARBs, azilsartan is proven to be more potent in most of the head-to-head trials to date. Azilsartan is the latest ARB approved for hypertension with greater potency and minimal side effects The drug has evolved to be the first-line choice in patients whose BP is not at goal despite combination therapy. (19)

• Cushman et al. compared azilsartan (40/80 mg) and chlorthalidone combination with olmesartan (40 mg) and hydrochlorothiazide combination in patients with stage 2 hypertension and evaluated mean ABPM (Systolic BP) pressure at 12 weeks. Azilsartan-based combination therapies lowered systolic BP (ABPM) better than olmesartan-based regimens. (20)

Choice of CCB-

• Nifedipine extended-release is a widely studied calcium channel blocker in hypertension. Recent data suggest that long-acting formulations of nifedipine have a greater antihypertensive action than amlodipine. (3)

• A noteworthy study evaluating the total anti-hypertensive power of the two drugs noted that the total anti-hypertensive power of nifedipine extended-release was about 1.69 times more potent than that of amlodipine. (21)

• A similar finding was put forth by Ryuzaki M et al, who found that Nifedipine (extended-release) had a stronger antihypertensive effect than amlodipine during the critical morning period.(22)

Choice of Diuretic-

• Studies have affirmed that among RH patients with moderate CKD, chlorthalidone (16) significantly reduces BP, exhibiting the greatest evidence base for reducing cardiovascular outcomes. An additional SBP reduction of 7 to 8 mm Hg has been noted simply by switching from hydrochlorothiazide to the same daily dose of chlorthalidone. (23,24,25)

• Loop diuretics are less effective than thiazide-type drugs in reducing hypertension in the nonedematous patient; however, As chronic kidney disease transitions from stage 3 to 5, particularly with extracellular fluid volume expansion, loop diuretic therapy becomes the preferred diuretic therapy for the management of hypertension. (26)

• In severe cases of CKD, torsemide scores far better than bumetanide or furosemide due to its prolonged half-life (3 to 4 hours) and longer duration of action (12 hours) compared to the others, enhancing the practicability of once-daily dosing. (27)

• Adding spironolactone as a 4th drug in resistant hypertension has often been cited to be an effective option. (26)

• Drug therapy for RH should be individualistic, tailored depending on the risk-benefit ratio, history of adverse events, contributing factors as well as co-morbidities.
• Identification of concomitant disease processes such as diabetes, CKD, sleep apnea, and atherosclerotic disease is compulsory for success in RH.
• As studies affirm, a triple-drug therapy comprising of an ARB, a CCB, and a diuretic has proved to be effective in managing RH.
• A rational choice of the drugs can go a long way in navigating through the disease successfully.

Conclusion-With accumulating evidence now highlighting a 96% reduction in cardiovascular events (3) with the use of triple antihypertensive regimens in RH patients, providing an optimized drug therapy is of key importance. As research continues to highlight the superior efficacy of triple-drug therapy in RH, the medical fraternity looks forward to managing this much-dreaded disease in the best possible way, in years to come.

The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Resistant Hypertension, click HERE


1. Wolf-Maier et al. Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA 289, 2363–2369 (2003).

2. Muntner Petal.ALLHAT Collaborative Research Group: Treatment-resistant hypertension and the incidence of cardiovascular disease and end-stage renal disease: Results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension 64: 1012–1021, 2014pmid:25259745

3. Carey RM, Calhoun DA, Bakris GL, Brook RD, Daugherty SL, Dennison-Himmelfarb CR, Egan BM, Flack JM, Gidding SS, Judd E, Lackland DT, Laffer CL, Newton-Cheh C, Smith SM, Taler SJ, Textor SC, Turan TN, White WB; on behalf of the American Heart Association Professional/Public Education and Publications Committee of the Council on Hypertension; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Genomic and Precision Medicine; Council on Peripheral Vascular Disease; Council on Quality of Care and Outcomes Research; and Stroke Council. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension. 2018;72:e53–e90. DOI: 10.1161/HYP.0000000000000084

4. Egan BM, Kai B, Wagner CS, Henderson JH, Chandler AH, Sinopoli A. Blood pressure control provides less cardiovascular protection in adults with than without apparent treatment-resistant hypertension. J Clin Hypertens (Greenwich). 2016;18:817–824. doi: 10.1111/jch.12773 [PubMed:26856795]

5. Bangalore, S., Davis, B. R., Cushman, W. C., Pressel, S. L., Muntner, P. M., Calhoun, D. A., Kostis, J. B., Whelton, P. K., Probstfield, J. L., Rahman, M., Black, H. R., & ALLHAT Collaborative Research Group (2017). Treatment-Resistant Hypertension and Outcomes Based on Randomized Treatment Group in ALLHAT. The American journal of medicine, 130(4), 439–448.e9.

6. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, Giles TD, Falkner B, Carey RM; American Heart Association Professional Education Committee. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008 Jun 24;117(25):e510-26. doi: 10.1161/CIRCULATIONAHA.108.189141. PMID: 18574054.

7. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Hypertension. 2018;71:e140–e144]. Hypertension. 2018;71:e13–e115. doi: 10.1161/HYP.0000000000000065

8. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, Jones DW, Kurtz T, Sheps SG, Roccella EJ. Recommendations for blood pressure measurement in humans and experimental animals, part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Circulation. 2005;111:697–716. doi: 10.1161/01.CIR.0000154900.76284.F6

9. Yaxley, J. P., & Thambar, S. V. (2015). Resistant hypertension: an approach to management in primary care. Journal of family medicine and primary care, 4(2), 193–199.

10. Borghi C, Tubach F, De Backer G, Dallongeville J, Guallar E, Medina J, Perk J, Roy C, Banegas JR, Rodriguez-Artalejo F, Halcox JP. Lack of control of hypertension in primary cardiovascular disease prevention in Europe: results from the EURIKA study. Int J Cardiol. 2016;218:83–88. doi: 10.1016/j.ijcard.2016.05.044

11. Franz H. Messerli, Sripal Bangalore, Treatment-resistant hypertension: another Cinderella story, European Heart Journal, Volume 34, Issue 16, 21 April 2013, Pages 1175–1177,

12. Bharatia R, Chitale M, Saxena GN, Kumar RG, Chikkalingaiah, Trailokya A, Dalvi K, Talele S. Management Practices in Indian Patients with Uncontrolled Hypertension. J Assoc Physicians India. 2016 Jul;64(7):14-21. PMID: 27759337.

13. Sim JJ, Bhandari SK, Shi J, Reynolds K, Calhoun DA, Kalantar-Zadeh K, Jacobsen SJ.

Comparative risk of renal, cardiovascular, and mortality outcomes in controlled, uncontrolled resistant, and nonresistant hypertension. Kidney Int. 2015;88:622–632. doi: 10.1038/ki.2015.142[PubMed: 25945406]

14. Lloyd-Jones DM, Evans JC, Larson MG, O'Donnell CJ, Rocella EJ, Levy D. Differential control of systolic and diastolic blood pressure: factors associated with lack of blood pressure control in the community. Hypertension. 2000; 36: 594–599.

15. Cushman WC, Ford CE, Cutler JA, Margolis KL, Davis BR, Grimm RH, Black HR, Hamilton BP, Holland J, Nwachuku C, Papademetriou V, Probstfield J, Wright JT, Alderman MH, Weiss RJ, Piller L, Bettencourt J, Walsh SM, for the ALLHAT Collaborative Research Group. Success and predictors of blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering and Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens. 2002; 4: 393–404. Crossref.

16. Nishizaka MK et al. Validity of plasma aldosterone-to-renin activity ratio in African American and white subjects with resistant hypertension. Am J Hypertens. 2005;18:805–812.

17. Parthasarathy HK, Ménard J, White WB, Young WF Jr, Williams GH, Williams B, Ruilope LM, McInnes GT, Connell JM, MacDonald TM. A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism. J Hypertens. 2011;29:980–990. doi: 10.1097/HJH.0b013e3283455ca5 [PubMed: 21451421]

18. White WB, Weber MA, Sica D, Bakris GL, Perez A, Cao C, Kupfer S. Effects of the angiotensin-receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension. Hypertension. 2011;57:413–420. doi:10.1161/HYPERTENSIONAHA.110.163402 [PubMed: 21282560]

19. Akshyaya Pradhan, Ashish Tiwari, Rishi Sethi, "Azilsartan: Current Evidence and Perspectives in Management of Hypertension", International Journal of Hypertension, vol. 2019, Article ID 1824621, 8 pages, 2019.

20. W. C. Cushman, G. L. Bakris, W. B. White et al., "Azilsartan medoxomil plus chlorthalidone reduces blood pressure more effectively than olmesartan plus hydrochlorothiazide in stage 2 systolic hypertension," Hypertension, vol. 60, no. 2, pp. 310–318, 2012.

21. Kuga, K., Xu, D. Z., Ohtsuka, M., Aonuma, K., Lau, A. H. C., Watanabe, Y., & Ohtsuka, K. (2011). Comparison of Daily Anti-Hypertensive Effects of Amlodipine and Nifedipine Coat-Core Using Ambulatory Blood Pressure Monitoring - Utility of"Hypobaric Curve"and"Hypobaric Area." Clinical and Experimental Hypertension, 33(4), 231–239. doi:10.3109/10641963.2011.583968

22. Ryuzaki M, Nakamoto H, Nishida E, Sone M, Nakajima S, Yoshimoto M, Suzuki Y, Itagaki K. Crossover study of amlodipine versus nifedipine CR with home blood pressure monitoring via cellular phone: internet-mediated open-label crossover trial of calcium channel blockers for hypertension (i-TECHO trial). J Hypertens. 2007 Nov;25(11):2352-8. doi: 10.1097/HJH.0b013e3282ef7adc. PMID: 17921832.

23. Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJ, Phillips BB, Zimmerman MB, Bergus GR.Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension. 2006;47:352–358. doi: 10.1161/01.HYP.0000203309.07140.d3 [PubMed: 16432050]

24. Khosla N, Chua DY, Elliott WJ, Bakris GL. Are chlorthalidone and hydrochlorothiazide

25. equivalent blood-pressure-lowering medications? J Clin Hypertens (Greenwich). 2005;7:354–356. [PubMed: 16088299]

26. George C. Roush, Domenic A. Sica, Diuretics for Hypertension: A Review and Update, American Journal of Hypertension, Volume 29, Issue 10, October 2016, Pages 1130–1137,

27. Agarwal R, Sinha A, D, Pappas M, K, Ammous F: Chlorthalidone for Poorly Controlled Hypertension in Chronic Kidney Disease: An Interventional Pilot Study. Am J Nephrol 2014;39:171-182. doi: 10.1159/000358603


Disclaimer: This site is primarily intended for healthcare professionals. Any content/information on this website does not replace the advice of medical and/or health professionals and should not be construed as medical/diagnostic advice/endorsement or prescription. Use of this site is subject to our terms of use, privacy policy, advertisement policy. © 2020 Minerva Medical Treatment Pvt Ltd

Our comments section is governed by our Comments Policy . By posting comments at Medical Dialogues you automatically agree with our Comments Policy , Terms And Conditions and Privacy Policy .

Similar News