Management of resistant hypertension (RH), defined as uncontrolled blood pressure on three or more antihypertensive medications including a diuretic, begins initially with identifying and addressing contributors such as medication adherence, lifestyle factors and the use of interfering substances. Evaluation for the “white-coat” phenomenon, or associated conditions and secondary causes such as sleep apnea, primary aldosteronism, chronic kidney disease or renovascular disease may be indicated. Inadequate dosing, lack of using long-acting diuretics, and suboptimal combinations are observed as causes in nearly half of patients with RH. Appropriate pharmacotherapy of RH begins first with insuring the patient is receiving appropriate therapy for compelling indications, as outlined by the JNC-7 guidelines. Specific regimen enhancements to achieve blood pressure control include the addition of aldosterone antagonists, dual renin-angiotensin system blockade, and dual calcium channel blockade. Addition of centrally acting agents, alpha blockers, or vasodilators may also be necessary.
* Managing resistant hypertension (RH) begins initially with identifying and intervening on reversible contributing factors such as medication adherence, lifestyle factors and investigating the use of interfering substances.
* Further work-up to exclude secondary causes or assess for the “white-coat” phenomenon may be indicated.
* Ineffective regimens, including inadequate dosing, lack of using long-acting diuretics, and suboptimal combinations are observed as causes in nearly half of patients with RH.
* Appropriate pharmacotherapy of RH begins with insuring that the patient is receiving appropriate therapy for compelling indications as outlined by the JNC-7 guidelines.
* Specific regimen enhancements to achieve blood pressure control include the addition of aldosterone antagonists, dual renin-angiotensin system blockade, dual calcium channel blockade, alpha blockers, combined alpha/beta blockers, centrally acting agents, and vasodilators.
1. Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. JAMA 2003;290:199–206.
2. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA 2003;289:2560–2572.
3. Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens 2002;4:393–399.
4. Moser M, Setaro JF. Resistant or difficult-to-control hypertension. N Engl J Med 2006;355:385–392.
5. Redon J, Campos C, Narciso ML, et al. Prognostic value of ambulatory blood pressure monitoring in refractory hypertension: a prospective study. Hypertension 1998;31:712–718.
6. Brown MA, Buddle ML, Martin A. Is resistant hypertension really resistant? Am J Hypertens 2001;14:1263–1269.
7. Calhoun DA, Zaman MA, Nishizaka MK. Resistant hypertension. Curr Hypertens Rep 2002;4:221–228.
8. Pickering TG, Shimbo D, Haas D. Ambulatory blood-pressure monitoring. N Engl J Med 2006;354:2368–2374.
9. Caro JJ, Speckman JL, Salas M. Effect of initial drug choice on persistence with antihypertensive therapy: the importance of actual practical data. CMAJ 1999;160:41–46.
10. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353:487–497.
11. Krousel-Wood M, Thomas S, Muntner P, et al. Medication adherence: a key factor in achieving blood pressure control and good clinical outcomes in hypertensive patients. Curr Opin Cardiol 2004;19:357–362.
12. Bremner AD. Antihypertensive medication and quality of life: silent treatment of a silent killer? Cardiovasc Drugs Ther 2002;16:353–364.
13. Phillips LS, Branch WT, Cook CB, et al. Clinical inertia. Ann Intern Med 2001;135:825–384.
14. Berlowitz DR, Ash AS, Hickey EC, et al. Inadequate management of blood pressure in a hypertensive population. N Engl J Med 1998;339:1957–1963.
15. Oliveria SA, Lapuerta P, McCarthy BD, et al. Physician-related barriers to the effective management of uncontrolled hypertension. Arch Intern Med 2002;162:413–420.
16. Lloyd-Jones DM, Evans JC, Larson MG, et al. Differential control of systolic and diastolic blood pressure: factors associated with lack of blood pressure control in the community. Hypertension 2000;36:594–599.
17. Aucott L, Poobalan A, Smith WC, et al. Effects of weight loss in overweight/obese individuals and long-term hypertension outcomes: a systematic review. Hypertension 2005;45:1035–1041.
18. Appel LJ, Brands MW, Daniels Sr, et al. Dietary approaches to prevent and treat hypertension: a scientific statement from the American Heart Association. Hypertension 2006;47:296–308.
19. Logan Ag, Perlikowski SM, Mente A, et al. High prevalence of unrecognized sleep apnea in drug-resistant hypertension. J Hypertension 2001;19:2271–2277.
20. Safian RD, Textor SC. Renal-artery stenosis. N Eng J Med 2001;344:431–442.
21. Calhoun DA, Nishizaka MK, Zaman MA, et al. High prevalence of primary aldosteronism among black and white subjects with resistant hypertension. Hypertension 2002;40:892–896.
22. Garg JP, Elliott WJ, Folker A, et al. RUSH University Hypertension Service: resistant hypertension revisited: a comparison of two university- based cohorts. Am J Hypertens 2005;18:619–626.
23. Williams B, Poulter NR, Brown MJ, et al. British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary. BMJ 2004;328:634–640.
24. Ernst ME, Goerdt CJ, Carter BL, et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension 2006;47:352–358.
25. Khosla N, Chua DY, Elliott WJ, et al. Are chlorthalidone and hydrochlorothiazide equivalent blood-pressure-lowering medications? J Clin Hypertens 2005;7:354–356.
26. Brown MJ, Cruickshank JK, Dominiczak AF, et al. Better blood pressure control: how to combine drugs. J Hum Hypertens 2003;17:81–86.
27. Belz GG, Breithaupt K, Erb K, et al. Influence of the angiotensin converting enzyme inhibitor cilazapril, the beta blocker propranolol and their combination on haemodynamics in hypertension. J Hypertens 1989;7:817–824.
28. Bakris GL, Williams M, Dworkin L, et al. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group: preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis 2000;36:646–661.
29. Nishizaka MK, Calhoun DA. The role of aldosterone antagonists in the management of resistant hypertension. Curr Hypertens Rep 2005;7:343–347.
30. Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens 2003;16:925–930.
31. Chapman N, Dobson J, Wilson S, et al. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 2007;49:839–845.
32. Weinberger MH, Roniker B, Krause SL, et al. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens 2002;15:709–716.
33. Flack JM, Oparil S, Pratt JH, et al. Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients. J Am Coll Cardiol 2003;41:1148–1155.
34. Krum H, Nolly H, Workman D, et al. Efficacy of eplerenone added to renin-angiotensin blockade in hypertensive patients. Hypertension 2002;40:117–123.
35. Prisant LM, Krum H, Roniker B. Can renin status predict the antihypertensive efficacy of eplerenone add-on therapy? J Clin Pharmacol 2003;43:1203–1210.
36. van den Meiracker AH, Man in’t Veld AJ, Admiraal PJ, et al. Partial escape of angiotensin converting enzyme (ACE) inhibition during prolonged ACE inhibitor treatment: does it exist and does it affect the antihypertensive response? J Hypertens 1992;10:803–812.
37. Sica DA, Elliott WJ. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in combination: theory and practice. J Clin Hypertens 2001;3:383–387.
38. Finnegan PM, Gleason BL. Combination ACE inhibitors and angiotensin II receptor blockers for hypertension. Ann Pharmacother 2003;37:886–889.
39. Mogensen CE, Neldam S, Tikkanen I, et al. CALM study group: randomized controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000;321:1440–1444.
40. Saseen JJ, Carter BL, Brown TE, et al. Comparison of nifedipine alone and with diltiazem or verapamil in hypertension. Hypertension 1996;28:109–114.
41. Kaesemeyer WH, Carr AA, Bottini PB, et al. Verapamil and nifedipine in combination for the treatment of hypertension. J Clin Pharmacol 1994;34:48–51.
42. National Kidney Foundation. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004;43(suppl 1):S1–S290.
43. Sica DA. Minoxidil: an underused vasodilator for resistant or severe hypertension. J Clin Hypertens 2004;6:283–287.
44. Fries E. Hypertension treatment: contributions and comments on challenges. J Clin Hypertens 2004;6:45–46.