Treatment modalities

The goal BP in all hypertensive patients is <140/90 mm Hg. There is evidence supporting a lower BP goal in patients with stage 3 or higher CKD, if 
>300 mg/day of proteinuria is present. The 2008 AHA guidelines recommend both nonpharmacologic and pharmacologic therapies for treatment.7,38

Nonpharmacologic interventions

Lifestyle changes, including weight loss, regular exercise, ingestion of a high fiber, low fat, and low-salt diet (of primary importance), and moderate alcohol intake should be strongly encouraged. Excessive sodium and excessive weight—along with poor sleep habits—are most commonly associated with RH. A recent weight loss study showed that a 10 kg weight loss is associated with an average of 6.0 mm Hg reduction of SBP. Morbidly obese patients who have failed to lose more than 10-15 pounds should be referred for surgical evaluation.39, 40

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The benefit of salt reduction is well documented in general HT patients. Salt restriction to <3 grams/day is associated with modest reductions in BP. Current guidelines suggest that dietary sodium in HT patients should be <100 mmol/day (2.4 gm of sodium or 6 g sodium chloride).41, 42 Alcohol intake should be limited to no more than one ounce of ethanol/day in most men (~2 drinks) and 0.5 ounce of ethanol/day in women and lighter-weight individuals.43 Ingestion of a diet rich in fruits and vegetables, high in low-fat dairy products, potassium, magnesium, calcium, and low in total saturated fats was found to reduce BP by 11.4/5.5 mm Hg.44-46

Pharmacologic treatment

Pharmacologic treatment involves meaningful use of three different antihypertensive medications titrated to the maximally tolerated dose, one of which is a diuretic appropriate for the level of kidney function. Recommendations in the modification and intensification of treatment are based on pharmacologic principles in the context of the underlying pathophysiology of HT, the clinical experience of the physician, and treatment guidelines.

The present rationale is to ensure that all mechanisms for BP elevation are blocked by maximizing treatment.47-49 The patient’s regimen should be simplified using long-acting fixed-dose 
combination agents when possible, to improve adherence, reduce pill counts, and permit once-daily dosing.

In keeping with the recent NICE BP guidelines, most patients should be on a renin-angiotensin-aldosterone (RAAS) system blocker, along with a calcium antagonist, and an appropriately-dosed diuretic. The physician must ensure that these agents are prescribed at maximally-tolerated doses and may exceed dose limits in morbidly obese patients.

This triple regimen of an angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB), long-acting CCB, and a long-acting diuretic—preferably chlorthalidone or indapamide— is often effective and well tolerated by patients. This triple regimen can be given as two pills with the wide variety of available fixed-dose combinations.25,50

Combining an ACE-I with ARB was less effective in terms of BP reduction than adding a diuretic or a CCB, and did not reduce CV or renal events.51,52 In a separate trial, the combination of the direct renin inhibitor, aliskiren, and an ARB was also associated with a small additional BP drop,53 but no outcome data are available. Thus, dual RAAS blockade is not recommended.

Cornerstones of treatment

An appropriate diuretic remains the cornerstone of treatment, as persistent volume expansion contributes to RH. In 279 patients taking thiazide diuretics, researchers saw a significant increase in levels of brain natriuretic peptide and atrial natriuretic peptide among RH patients, suggesting volume expansion.54

Chlorthalidone is preferred over hydrochlorothiazide (HCTZ) for treatment, the former appearing to have more potency than the latter drug. Greater ambulatory BP reduction was demonstrated with chlorthalidone, 
25 mg once daily, with the largest difference occurring overnight, as compared to a 50 mg daily dose of the HCTZ.55 Switching HCTZ users to chlorthalidone resulted in an additional 
8 mm Hg drop, and an increased number of patients reaching BP goal.56

Chlorthalidone is initially recommended at 12.5 mg once a daily, with subsequent titration up to 25 mg daily. It is necessary to monitor serum electrolytes; however, this is generally given with an ARB or ACE-I so the risk of hypokalemia is very low unless the patient is nonadherent with sodium restriction. Among patients with an estimated glomerular filtration rate 
<40 mL/min/1.73m2, thiazide diuretics are less effective. Loop diuretics, such as furosemide or torsemide (preferred due to longer action), are necessary for effective volume control.7

The Systolic Hypertension in Europe (Syst-Eur) trial also has a great deal of outcome data on indapamide, demonstrating risk reduction for both heart failure and strokes. Indapamide also has a lower side effect profile compared to chlorthalidone. When given in doses of 2.5 mg daily, it has proven effective.

Adding aldosterone antagonists provides significant benefit to existing drug regimens in patients with RH, as these patients were found to have higher levels of plasma aldosterone. In a study of patients on an average of four antihypertensive medications, the addition of spironolactone resulted in an average of 25/12 mm Hg reduction of BP after six months of treatment.57 In the BP lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), patients receiving spironolactone as a fourth line antihypertensive medication for uncontrolled BP resulted in a 21.9/9.5 mm Hg drop in BP regardless of age, sex, smoking and presence of diabetes.58,59

The advantage of using spironolactone is that it can lower BP even with normal or low aldosterone levels. The most common adverse effect of spironolactone is breast tenderness, particularly in men—especially in doses above 25 mg/day. This can be avoided by using a more selective mineralocorticoid receptor antagonist, eplerenone, which has demonstrated BP-lowering efficacy and can reduce proteinuria.60-62 Eplerenone must be given twice daily. 

Amiloride is another potassium-sparing diuretic associated with BP reduction. In a blinded comparison of amiloride 10 mg taken once daily, spironolactone 25 mg daily, or a combination of both used in African American patients on a two-drug regimen (a diuretic and a CCB), the mean decrease in BP was 12.2/4.8 mm Hg for amiloride, 7.3/3.3 mm Hg for spironolactone, and 14.1/5.1 mm Hg for the combination of both drugs.63

Hyperkalemia may occur when prescribing these agents, especially in combination with an ACE-I or ARB, thus necessitating close monitoring if kidney function is not within the normal range. Physicians should educate patients to avoid food and supplements rich in potassium, and to avoid medications such as NSAIDs.64

If the patient is still hypertensive on maximally tolerated doses of three or four drugs—including spironolactone—he should be referred to a board certified hypertension specialist. A directory of board certified specialists is available online at the American Society of Hypertension website. 

Vasodilating beta blockers (carvedilol, nebivolol, bisoprolol) may be used as fifth-line agents especially, if tachycardia i.e. resting heart rate >84 is present.65 Vasodilating beta blockers have fewer side effects compared to traditional beta blockers and are just as efficacious for lowering BP.66 Centrally-acting agents should not be used with beta blockers, as this provides little-to-no- additional BP lowering, if the beta blocker is maximally titrated.