Does this patient have resistant hypertension?

Resistant hypertension is classified as persistent hypertension (blood pressure [BP] >140/90 mm Hg) despite adherence to maximal doses of three antihypertensive agents (one of which should be a diuretic).

Strict adherence to antihypertensive medication is suboptimal. In one study, urine levels of antihypertensives were measured by mass spectrometry in patients with apparent resistant hypertension; over 50% of patients were considered nonadherent to their prescribed regimen. The provider should attempt to ensure that the patient is taking the appropriate medications before diagnosing resistant hypertension. Possible tools for assessing adherence include: pill diaries, consultation with pharmacy, discussion with family members, questioning about drug side effects.

History regarding environmental stimuli for hypertension should be obtained. Alcohol and salt intake should be estimated. Use of medications that cause hypertension such as oral contraceptives, nonsteroidal anti-inflammatory drugs (NSAIDs) (3/2 mm Hg increase), decongestants, and corticosteroids should be ascertained. The provider should also question the patient about illicit drug use, such as cocaine or methamphetamines.

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Correct measurement of BP is essential. The patient should be quietly seated for 5 minutes with their arm rested at heart level. Since inappropriately small cuffs may cause elevated blood pressure readings, the cuff bladder must encircle at least 80% of the upper arm circumference.

A focused physical exam should evaluate the patient for both secondary causes of hypertension (body mass index, unequal blood pressures on both arms, abdominal bruit, signs of Cushing’s disease, thyroid exam) and for signs of target organ damage (retinal changes, cardiac exam).

In the absence of target organ damage, to eliminate the possibility of white coat hypertension, home blood pressure readings or readings from an ambulatory 24-hour blood pressure monitor should corroborate the diagnosis of hypertension.

What tests to perform?

Most patients with resistant hypertension will have essential hypertension; however, patients with resistant hypertension are still more likely to have a secondary cause. A brief evaluation can help exclude secondary causes of hypertension. Assessment of renal function and proteinuria can help exclude parenchymal renal disease. Serum potassium and bicarbonate may offer clues to secondary causes of hypertension related to aldosterone excess (primary hyperaldosteronism, renal artery stenosis). Although controversial, some would recommend checking renin activity and aldosterone levels in all patients with resistant hypertension given prevalence (in some reports 10-20%).

If patient has symptoms of pheochromocytoma (episodic headaches, sweating, palpitations), check serum metanephrines. If patient is obese or has symptoms of sleep apnea, a formal sleep study is recommended. To estimate daily sodium intake, a 24-hour urine collection for sodium may be helpful.

Imaging

If there is concern for renal artery stenosis (flash pulmonary edema, renal failure after angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), unexplained renal failure), consider imaging for renal artery stenosis: captopril renal scan, computed tomography (CT) angiography, magnetic resonance (MR) angiography.

If there is a high aldosterone:renin ratio and aldosterone levels do not suppress with saline, CT scan of abdomen or adrenal vein sampling can help to further evaluate for adrenal adenoma.

Biopsy

A renal biopsy is unlikely to help in the management of resistant hypertension unless there is concern for an undiagnosed glomerulonephritis.

Overall interpretation of test results

If patient has decreased glomerular filtration rate (GFR:<40-50 ml/min), volume overload is a likely culprit and attention needs to paid to correct diuretic (usually loop diuretic) and correct dose. Test results consistent with primary hyperaldosteronism should prompt therapy with aldosterone antagonist or referral for removal of unilateral adrenal adenoma, both of which should lead to a significant decrease in blood pressure. A high 24-hour urine sodium excretion should prompt education on a reduced sodium diet; lowering dietary sodium can have strong effects in subpopulations of patients with resistant hypertension.

How should patients with resistant hypertension be managed?

Rule out of pseudo-resistant hypertension (white coat hypertension, medication compliance). White coat hypertension can be seen in as many as 20% of patients with “resistant hypertension.” Assess for secondary causes including medications (see above).

If 24-hour urine reveals elevated dietary sodium, change to low sodium diet. Switching from a high salt diet to low salt diet has been associated with a 20/10-point reduction in BP.

Although not specifically studied in resistant hypertension, alcohol reduction in heavy alcohol users has been associated with a 7/6 mm Hg decrease in blood pressure.

In patients with hypertension, 10% weight loss can decrease SBP by 6-7 points. According to a meta-analysis of randomized trials, CPAP therapy can lower BP by an average of 2.5/1.8 mm Hg in all patients although those who tolerate it for the entire night have greater than 5 mm Hg drop in systolic BP.

Consider switching short acting thiazide diuretic (hydrochlorothiazide) to long acting thiazide (chlorthalidone). In patients with reduced GFR (approximately less than 40 ml/min) switch from thiazide to loop diuretic. Short acting loop diuretics such as furosemide should be used twice daily. If patient is taking only a beta blocker consider switching to a combined alpha beta blocker, such as labetalol.

Add-on therapy with spironolactone may provide a significant benefit. In the ASCOT study, the patients with resistant hypertension experienced, on average, 20/10 mm Hg reduction in blood pressure. In a randomized, placebo-controlled trial of 111 patients with resistant hypertension, sprironolactone significantly decreased systolic BP (Vaclavik et al.). In a separate controlled. trial of patients with resistant hypertension, sprionolactone was more effective than doxazosin, bisoprolol, or placebo (Williams et al.).

Preliminary studies have shown that the endothelial antagonist darusentan can lower 24-hour BP in patients with RH by 10/8 mm Hg but leads to edema in 25% of patients.

Novel/experimental therapies

Renal sympathetic denervation has become a heavily studied therapy for resistant hypertension. In small, uncontrolled trials, nerve ablation appeared to lead to a large, durable decrease in blood pressure. The Symplicity HTN-3 trial was a randomized double blind trial utilizing a sham procedure. This trial enrolled 535 patients and had a strict enrollment criteria utilizing 24-hour ambulatory BP measurements and medication logs to ensure drug compliance. At 6 months, there was no significant decrease in BP with renal denervation. Currently, renal denervation cannot be recommended as therapy for resistant hypertension.

Carotid sinus stimulation devices have also been tested in an uncontrolled feasibility study. Forty-five patients were treated with a carotid stimulation device and then mean decrease in blood pressure at 3 months was 21/12 mm Hg.

What happens to patients with resistant hypertension?

  • In the largest series of patients with resistant hypertension, 20% of patients with resistant hypertension had abnormal renin:aldosterone ratio, 10% had true primary hyperaldosteronism, and more than 50% of those patients had a normal serum potassium. Although most patients with RH don’t have primary hyperaldosteronism, many do have hyperaldosteronism and can have dramatic responses to aldosterone antagonists

  • 50-75% of patients with resistant hypertension will have left ventricular hypertrophy (LVH)

  • Carotid intimal thickening is more common with resistant hypertension

  • Microalbuminuria appears to be more common

  • On 24-hour ambulatory blood pressure monitoring, “non-dipping” pattern at night is associated with higher rate of cardiovascular disease

  • In patients with true resistant hypertension (as opposed to patients with white coat hypertension), the risk of cardiovascular events is 3 to 4-fold higher

How to utilize team care?

  • In a randomized trial of patients with hypertension (not necessarily resistant hypertension), utilizing a pharmacist and nurse team led to 24 mm Hg drop in SBP in those patients with a SBP greater than 160 mm Hg

  • Dieticians can play an important role with education regarding low sodium diet

  • Instructional “story-telling” videos with ethnically similar patients has a significant effect on blood pressure

Are there clinical practice guidelines to inform decision making?

JNC VII guidelines:

  • Ensure appropriate BP measurement

  • Rule out secondary causes

  • Assess for competing substances and alcohol overuse

  • Measure BMI

  • Ensure euvolemia

  • Use appropriate dosage and combinations of anti-hypertensive agents

AHA guidelines:

  • Confirm treatment resistance

  • Identify and reverse lifestyle factors

  • Discontinue interfering substances

  • Screen for secondary causes

  • Pharmacologic Therapy

    Maximize diuretic therapy

    Combine agents with different mechanisms of action

    Use loop diuretics in patients with CKD and/or on potent vasodilators

  • Refer to specialist

Other considerations

  • ICD-9 Codes. 401.0 Malignant essential hypertension; hypertensive crises; resistant hypertension

What is the evidence?

Bhatt, DL, Kandzari, DE, O’Neill, WW. “A controlled trial of renal denervation for resistant hypertension.”. N Eng J Med.. vol. 370. 2014. pp. 1393-1401. (Symplicity HTN-3 Trial demonstrating no benefit to renal denervation.)

Calhoun, D, Jones, D, Textor, S, Goff, D, Murphy, T, Toto, R, White, A, Cushman, W, White, W, Sica, D, Ferninand, K, Giles, T, Falkner, B, Carey, R. “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. vol. 51. 2008. pp. 1403-1419. (American Heart Association guidelines regarding resistant hypertension. Article also provides a summary of evidence supporting guidelines.)

Chapman, N, Dobson, J, Wilson, S, Dahlof, B, Sever, PS, Wedel, H, Poulter, NR. “Effects of spironolactone on blood pressure in subjects with resistant hypertension.”. Hypertension. vol. 49. 2007. pp. 839-845. (Post-hoc analysis of the ASCOT trial. When spironolactone was added as a fourth antihypertensive agent, BP on average fell by 20/10 mm Hg.)

Bazzano, LA, Khan, Z, Reynolds, K, He, J. “Effect of nocturnal nasal continuous positive airway pressure on blood pressure in obstructive sleep apnea.”. Hypertension. vol. 50. 2007. pp. 417-423. (Meta-analysis of randomized, controlled studies using CPAP for OSA and measuring blood pressure. Sixteen trials were included. On average, CPAP was associated with a drop in BP of 2.5/1.8 mm Hg.)

Braam, B, Taler, S.J, Rahman, M, Fillaus, J, Greco, B, Forman, J, Reisin, E, Cohen, D, Saklayen, M, Hedayati, S. “Recognition and management of resistant hypertension.”. Clin J Am Soc Nephrol. vol. 12. 2017. pp. 524-535. (Review article covering management of resistant hypertension)

de Souza, F, Muxfeldt, E, Fiszman, R, Salles, G. “Efficacy of spironolactone therapy in patients with true resistant hypertension.”. Hypertension.. vol. 55. 2010. pp. 147-152. (Uncontrolled study showing that addition of spironolactone to patients with true resistant hypertension leads to significant decreases in blood pressure.)

Douma, S, Petidis, K, Doumas, M, Papaefthimiou, P, Triantafyllou, A, Kartali, N, Papadopoulos, N, Vogiatzis, K, Zamboulis, C. “Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study.”. Lancet. vol. 371. 2008. pp. 1921-1926. (Observational study of patients referred to tertiary clinic for resistant hypertension. 11% had primary hyperaldosteronism as diagnosed by salt suppression test; less than 50% of those with primary hyperaldosteronism had hypokalemia.)

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. vol. 47. 2006. pp. 352-358. (Randomized controlled trial comparing chlorthalidone (12.5 mg/day) and hydrochlorothiazide (25 mg /day) in untreated hypertensive patients. Ambulatory blood pressure measurements showed a greater reduction in BP with chlorthalidone.)

Houston, TK, Allison, JJ, Sussman, M, Horn, W, Holt, CL, Trobaugh, J, Salas, M, Pisu, M, Cuffee, YL, Larkin, D, Person, SD, Barton, B, Kiefe, CI, Hullet, S. “Culturally appropriate storytelling to improve blood pressure: a randomized trial.”. Ann Intern Med. vol. 154. 2011. pp. 77-84. (Randomized, controlled trial using culturally similar “storytellers” to educate patients with HTN. There was a significant BP reduction with intervention.)

Jung, O, Gechter, JL, Wunder, C, Paulke, A, Bartel, C, Geiger, H, Toennes, SW. “Resistant hypertension? Assessment of adherence by toxicological urine analysis.”. J Hypertens. vol. 31. 2013. pp. 766-774. (To assess drug adherence in patients with apparent resistant hypertension, urine antihypertensive levels were measured using mass spectrometry. Over half of the patients exhibited suboptimal medication adherence.)

McLean, DL, McAlister, FA, Johnson, JA, King, KM, Makowsky, MJ, Jones, CA, Tsuyuki, RT. “A randomized trial of the effect of community pharmacist and nurse care on improving blood pressure management in patients with diabetes mellitus: study of cardiovascular risk intervention by pharmacists-hypertension (SCRIP-HTN).”. Arch Intern Med. vol. 168. 2008. pp. 2355-2361. (Randomized, controlled trial using an intervention of a nurse and pharmacist to assist with BP control. The intervention led to a decrease in SBP of 5.6 mm Hg.)

Pimenta, E, Gaddam, KK, Oparil, S, Aban, I, Husain, S, Dell’Italia, LJ, Calhoun, DA. “Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension: results from a randomized trial.”. Hypertension. vol. 54. 2009. pp. 475-481. (Small, crossover study of patients with resistant hypertension. As compared to a high sodium diet, a low sodium diet decreased BP by 23/9 mm Hg.)

Moser, M, Setaro, JF. “Clinical practice. Resistant or difficult-to-control hypertension.”. N Eng J Med. vol. 355. 2006. pp. 385-392. (Review article regarding evaluation and management of resistant hypertension.)

Parker, MG. “Resistant hypertension: Core Curriculum 2008.”. Am J Kidney Dis. vol. 52. 2008. pp. 796-802. (Outline covering causes and management of resistant hypertension.)

Pisoni, R, Ahmed, MI, Calhoun, DA. “Characterization and treatment of resistant hypertension.”. Curr Cardiol Rep. vol. 11. 2009. pp. 407-413. (Review article regarding evaluation and management of resistant hypertension.)

Scheffers, IJ, Kroon, AA, Schmidli, J, Jordan, J, Tordoir, JJ, Mohaupt, MG. “Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study.”. J Am Coll Cardiol. vol. 56. 2010. pp. 1254-1258. (Prospective, safety study of carotid baroreflex activator. On average, after 3 months, BP was reduced by 21/12 mm Hg.)

Stevens, VJ, Corrigan, SA, Obarzanek, E, Bernauer, E, Cook, NR, Hebert, P, Mattfeldt-Beman, M, Oberman, A, Sugars, C, Dalcin, AT. “Weight loss intervention in phase 1 of the Trials of Hypertension Prevention. The TOHP Collaborative Research Group.”. Arch Intern Med. vol. 153. 1993. pp. 849-858. (Randomized, controlled trial studying effect of weight loss on blood pressure. Weight loss of about 5 kg was associated with a reduction in BP of 3.1/2.8 mm Hg in men and 2.0/1.1 mm Hg in women.)

Vaclavik, J, Sedlak, R, Jarkovsky, J, Kocianova, E, Taborsky, M. “Effect of spironolactone in resistant arterial hypertension: A randomized, double-blind, placebo-controlled trial (ASPIRANT-EXT).”. Medicine (Baltimore). vol. 93. 2014. pp. e162(Trial showing spironolactone is more effective than placebo in patients with resistant hypertension.)

White, WB. “Cardiovascular effects of the cyclooxygenase inhibitors.”. Hypertension,. vol. 49. 2007. pp. 408-418. (Review article covering NSAIDs and COX inhibitors and effects on blood pressure.)

Williams, B, MacDonald, TM, Morant, S, Webb, DJ, Sever, P, McInnes, G, Ford, I, Cruickshank, JK, Caulfield, MJ, Salsbury, J, Mackenzie, I, Padmanabhan, S, Brown, MJ. “British Hypertension Society’s PATHWAY Studies Group: Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): A randomised, double-blind, crossover trial.”. Lancet. vol. 386. 2015. pp. 2059-2068. (Trial comparing spironolactone to bisoprolol or doxazosin in patients with resistant hypertension.)?

Xin, X, He, J, Frontini, MG, Ogden, LG, Motsamai, OI, Whelton, PK. “Effects of alcohol reduction on blood pressure: a meta-analysis of randomized controlled trials.”. Hypertension. vol. 38. 2001. pp. 1112-1117. (Meta-analysis covering trials with alcohol reduction and measurement of blood pressure. Alcohol reduction was associated with a 3/2 mm Hg reduction in BP.)

“Hypertension,”. vol. 57. 2011. pp. 911-917. (Prospective study of 45 patients undergoing renal sympathetic denervation (RSD). RSD was associated with a durable reduction in BP.)

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