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resistant hypertension; refractory hypertension

blood pressure that remains above goal despite treatment with optimal doses of 3 antihypertensives of different classes, including a diuretic (also see secondary hypertension) or uncontrolled blood pressure on >= 4 drugs [20] Etiology: - primary hyperaldosteronism (22% of patients with resistant hypertension) [20] - renovascular hypertension (renal artery stenosis) - chronic kidney disease (ESRD) - pheochromocytoma [1] - obstructive sleep apnea [8,9,17] (up to 83%) - medication non-compliance - consumption of substances that aggravate hypertension - dietary salt - excessive alcoholic beverage - nonsteroidal anti-inflammatory drugs - licorice - decongestants - pseudoephedrine - phenylephrine [1,5] - white coat hypertension Epidemiology: - 20% of patients with chronic hypertension [20] Laboratory: - plasma aldosterone/plasma renin activity (see below) - serum K+: hypokalemia inconsistently associated with primary hyperaldosteronism - angiotensin-2 in plasma - captopril-renin stimulation test - plasma free metanephrines &/or 24 hour urine metanephrines Special laboratory: - ambulatory blood pressure monitoring* (distinguishes from white-coat hypertension) [1,4] - renal ultrasound for renal artery stenosis - sleep study (polysomnography) for obstructive sleep apnea * first line testing (prior to plasma aldosterone/plasma renin activity) * see hypertension for AHA/ACC ambulatory blood pressure classification note BP goals for ambulatory blood pressure may differ from those of office blood pressure [1] Differential diagnosis: - white-coat hypertension (1/3 of cases) [2] - secondary hypertension Management: 1) see treatment of chronic hypertension - patient presumably on ACE inhibitor or ARB, calcium channel blocker & a thiazide diuretic or loop diuretic - if patient not on diuretic, prescribe one unless ESRD - if patient not on a calcium channel blocker, prescribe one 2) general a) confirm out-of-office BP measurement [1] a) life-style modifications - low sodium diet (< 2400 mg/day) - achieve ideal body weight - ensure adequate sleep hygiene, at least 6 hours/night [15] - aerobic exercise reduces 24-hour & daytime ambulatory blood pressure & office systolic systolic blood pressure [21] b) discontinue offending medications include OTC [1,5] c) correct underlying cause(s) 3) pharmaceuticals - if medication noncompliance suspected, discontinue medications dosed > QD - pre-packaging patient's pills in a blister pack less important than once a day dosing & including a dihydropyridine calcium channel blocker - addition of antihypertensive of a new class may be of benefit [14] - consider switching HCTZ to chlorthalidone or indapamide [15] - chlorthalidone more effective than hydrochlorothiazide [17] - switch thiazide diuretic to loop diuretic if eGFR < 20 mL/min - mineralocorticoid receptor antagonist if hyperaldosteronism [20] - spironolactone as add on [11] - spironolactone not inferior to clonidine & it is QD [13] - inferior to renal artery angioplasty with fibromuscular dysplasia [1] - amiloride noninferior to spironolactone [24] - lorundrostat (investgational aldosterone inhibitor) - baxdrostat 1 or 2 mg (investgational aldosterone inhibitor) [25] 4) renal sympathetic denervation [3] - renal denervation device in the SYMPLICITY HTN-3 trial failed to lower systolic BP by > 10 mm Hg [3] - of no benefit [7] 5) arterial-venous Coupler device that mechanically lowers systolic blood pressure via AV anastomosis shows promise [10] Notes: - 29% of patients claiming complete adherence to therapy showed a marked blood pressure response when treatment was observed [18]

Interactions

disease interactions

General

chronic hypertension

References

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  2. de la Sierra A et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension 2011 May; 57:898. PMID: 21444835
  3. Krum H et al. Catheter-based renal sympathetic denervation for resistant hypertension: A multicentre safety and proof-of-principle cohort study. Lancet 2009 Mar 30; [e-pub ahead of print] PMID: 19332353 http://dx.doi.org/10.1016/S0140-6736(09)60566-3 - Doumas M and Douma S. Interventional management of resistant hypertension. Lancet 2009 Mar 30; PMID: 19332354 http://dx.doi.org/10.1016/S0140-6736(09)60624-3 - Symplicity HTN-2 Investigators Renal sympathetic denervation in patients with treatment- resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010 Dec 4; 376:1903 PMID: 21093036 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62039-9/fulltext - Doumas M, Douma S. Renal sympathetic denervation: the jury is still out. Lancet 2010 Dec 4; 376:1878 PMID: 21093037 - Brandt MC et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol 2012 Mar 6; 59:901. PMID: 22381425 - Zile MR and Little WC. Effects of autonomic modulation: More than just blood pressure. J Am Coll Cardiol 2012 Mar 6; 59:910. PMID: 22381426 - Krum H et al. Percutaneous renal denervation in patients with treatment- resistant hypertension: Final 3-year report of the Symplicity HTN-1 study. Lancet 2013 Nov 7 PMID: 24210779 - ClinicalTrials.gov Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN-3) http://clinicaltrials.gov/ct2/show/record/NCT01418261 - Meditronic News Release. Jan 9, 2014 Medtronic Announces U.S. Renal Denervation Pivotal Trial Fails to Meet Primary Efficacy Endpoint While Meeting Primary Safety Endpoint. http://newsroom.medtronic.com/phoenix.zhtml?c=251324&p=irol-newsArticle&ID=1889335&highlight=
  4. Calhoun DA, Jones D, Textor S et al 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. Hypertension. 2008 Jun;51(6):1403-19. PMID: 18391085
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  10. Lobo MD et al Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial. Lancet. Jan 22, 2015 PMID: 25620016 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2962053-5/abstract
  11. Williams B et al Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. Sept 2015 PMID: 26414968 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2815%2900257-3/abstract http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2815%2900257-3/fulltext
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  13. Krieger EM, Drager LF, Giorgi DMA et al. Spironolactone versus clonidine as a fourth-drug therapy for resistant hypertension: The ReHOT randomized study (Resistant Hypertension Optimal Treatment). Hypertension 2018 Apr; 71:681 PMID: 29463627 http://hyper.ahajournals.org/content/71/4/681
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  15. Carey RM, Calhoun DA, Bakris GL et al Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association. Hypertension. Sept 13, 2018 PMID: 30354828 https://www.ahajournals.org/doi/10.1161/HYP.0000000000000084
  16. Braam B, Taler SJ, Rahman M et al Recognition and Management of Resistant Hypertension. Clin J Am Soc Nephrol. 2017 Mar 7;12(3):524-535. Review. PMID: 27895136 Free PMC Article
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  18. Ruzicka M, Leenen FHH, Ramsay T et al. Use of directly observed therapy to assess treatment adherence in patients with apparent treatment-resistant hypertension. JAMA Intern Med 2019 Jun 17; PMID: 31206124 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2735985
  19. Khawaja Z, Wilcox CS. Role of the kidneys in resistant hypertension. Int J Hypertens 2011 Apr 5; 2011:143471 PMID: 21461391 Free PMC Article
  20. Cohen JB, Cohen DL, Herman DS et al. Testing for primary aldosteronism and mineralocorticoid receptor antagonist use among U.S. veterans: A retrospective cohort study. Ann Intern Med 2020 Dec 29 PMID: 33370170 https://www.acpjournals.org/doi/10.7326/M20-4873
  21. Lopes S, Mesquita-Bastos J, Garcia C et al Effect of Exercise Training on Ambulatory Blood Pressure Among Patients With Resistant Hypertension. A Randomized Clinical Trial. JAMA Cardiol. Published online August 4, 2021. PMID: 34347008 https://jamanetwork.com/journals/jamacardiology/fullarticle/2782554
  22. Acelajado MC, Hughes ZH, Oparil S et al. Treatment of resistant and refractory hypertension. Circ Res. 2019;124(7):1061-1070 PMID: 30920924 PMCID: PMC6469348 Free PMC article https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.312156
  23. NEJM Knowledge+ Endocrinology
  24. Lee CJ, Ihm SH, Shin DH et al Spironolactone vs Amiloride for Resistant Hypertension: A Randomized Clinical Trial. JAMA. 2025 May 14:e255129. PMID: 40366680 https://jamanetwork.com/journals/jama/fullarticle/2834040 - Brook RD et al. New support for old medications in resistant hypertension. JAMA 2025 May 14 PMID: 40366665 https://jamanetwork.com/journals/jama/fullarticle/2834043
  25. Flack JM, Azizi M, Brown JM, et al. Efficacy and Safety of Baxdrostat in Uncontrolled and Resistant Hypertension. N Engl J Med. 2025 Aug 30 PMID: 40888730 PMCID: PMC7618089 https://www.nejm.org/doi/10.1056/NEJMoa2507109