New Therapeutic Options in Patients Prone to Hypertension: A Focus on Direct Renin Inhibition and Aldosterone Blockade

REVIEW ARTICLE

New Therapeutic Options in Patients Prone to Hypertension: A Focus on Direct Renin Inhibition and Aldosterone Blockade Jan Basile, MD

Abstract: Certain patient populations have a high prevalence of hypertension, including black, elderly, or obese patients; patients with metabolic syndrome, or frank diabetes; and patients with chronic kidney disease. Many of these patients experience renin-angiotensinaldosterone system (RAAS) dysregulation, which is important because the RAAS plays a pivotal role in the pathogenesis of hypertension, cardiovascular disease, and renal dysfunction. Data available regarding newer approaches that target the RAAS, including direct renin inhibition and aldosterone receptor antagonism, in patients who often have hypertension are reviewed. Aliskiren, the first direct renin inhibitor, is effective in a number of these patient groups, including those who are black or obese or who have metabolic syndrome, renal impairment, or diabetes. In addition, in the setting of long-term angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, aldosterone receptor antagonists (spironolactone and eplerenone) provide another rational therapeutic approach for patients whose blood pressure is not controlled by standard therapies. Key Indexing Terms: Hypertension; Renin inhibition; Aldosterone blockade. [Am J Med Sci 2009;337(6):438–444.]

H

ypertension affects more than 65 million people, or nearly one third of adults, in the United States.1,2 However, certain patient populations are at higher risk of hypertension. According to the 2003–2004 National Health and Nutrition Examination Survey (NHANES),1 among ethnic groups, nonHispanic black patients have the highest prevalence of hypertension (39.1%). The data from NHANES indicate that the risk factors for hypertension included education level, non-Hispanic black ethnicity, body mass index (BMI) (⬎25 kg/m2), and age (⬎40 years) (Figure 1).1 Historically, many of the patient groups who often have hypertension are at higher risk for cardiovascular and renal events than the general population. As recognized by the American Heart Association, these groups include black, elderly, or obese patients and patients with frank diabetes, chronic kidney disease, or high baseline blood pressure (BP).3 Because dysregulation of the renin-angiotensin-aldosterone system (RAAS) plays a critical role in the homeostatic control of arterial pressure, tissue perfusion, and extracellular volume,4 and in the pathogenesis of cardiovascular disease, renal dysfunction, and diabetes,5 interventions designed to inhibit the RAAS have been a cornerstone of antihypertensive therapy. This article will review the data regarding newer approaches through RAAS inhibition, including direct renin

From the Primary Care Service Line, Ralph H. Johnson VA Medical Center, Charleston, South Carolina; and Department of Medicine, Medical University of South Carolina, Charleston, South Carolina. Submitted May 20, 2008; accepted in revised form January 6, 2009. Correspondence: Jan Basile, MD, Primary Care Service Line, Ralph H. Johnson VA Medical Center, 109 Bee Street, Charleston, SC 29403 (E-mail: [email protected]).

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inhibitors (DRIs) and aldosterone blockers in the treatment of patients who often have hypertension. The Problem: Suboptimal Control of Hypertension Only two thirds of patients with hypertension in the NHANES (2003–2004)1 were aware of their condition; 54% received antihypertensive therapy, and of these patients, only 64% achieved adequate BP control (Figure 2). Control rates for treated patients remained particularly low for persons with diabetes (33%), elderly Mexican American men and women (44%), and elderly non-Hispanic black men and women (40%– 49%).1 Compared with BP control in nonHispanic white and Mexican American patients, BP control to target in non-Hispanic black patients was lower (Figure 3).1 According to the NHANES (1991–2000),6 BP control rates in treated patients 60 years and older ranged between 35% and 44%. Control rates were significantly lower during each of the survey periods for patients 60 years and older than for those 40 to 59 years of age [P ⫽ 0.03 (1988 –1991); P ⬍ 0.001 (1999 –2000)].6 Large randomized trials continue to produce better rates of BP control than those seen in the community. In the Controlled Onset Verapamil Investigation of Cardiovascular End Points7 and Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack8 trials, 66% of patients achieved BP control (⬍140/90 mm Hg) at the end of treatment through aggressive titration of antihypertensive therapy. Patients in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack8 trial received a mean of 2 antihypertensive agents, and 63% received 2 or more agents. Control of BP was consistently lower in patients with comorbid disorders, despite their greater use of multiple medications.8 Multiple regression analysis revealed that younger patients, men, patients who were not black, patients who did not have diabetes, leaner patients, patients with lower baseline systolic BP (SBP), patients without left ventricular hypertrophy, and patients not receiving treatment at entry were more likely to have better BP control than their reference groups. In particular, black patients were 31% less likely to achieve BP control than patients who were not black, most likely secondary to the absence of either a calcium channel blocker or a thiazide diuretic in one third of the participants.8 Because BP control is not achieved in many of these patient populations with a high prevalence of hypertension, new therapeutic options (either as monotherapy or in combination) are warranted. RAAS and Hypertension: Role for Direct Renin Inhibition and Aldosterone Blockade The RAAS plays an important role in the regulation of cardiovascular, renal, and adrenal functions by controlling arterial BP and salt balance by angiotensin II and electrolytes through aldosterone release.9,10 Figure 4 provides an overview

The American Journal of the Medical Sciences • Volume 337, Number 6, June 2009

DRI and Aldosterone Blockade in Treating Hypertension

‡ 27.35

Odds Ratio (95% Confidence Interval)

40

FIGURE 1. Odds ratios for the development of hypertension based on risk factors for hypertension.1 *P ⬍ 0.05, †P ⬍ 0.01, and ‡P ⬍ 0.001 for the independent association between hypertension prevalence and each factor after adjusting for the remaining factors. BMI, body mass index.

35 30 25 20 15

‡

10 5

‡

†

1.41

1.61

1.73

Less Than High School Education

Non-Hispanic Black

BMI 25-29 kg/m2

*

‡

6.04

3.39

0

of the RAAS cascade. Renin, an aspartyl protease produced in the juxtaglomerular cells of the kidney, is released in response to decreased perfusion pressure, decreased sodium chloride, and increased sympathetic activity.4 Renin secretion is the key mediator of RAAS activity because the renin-mediated conversion of angiotensinogen to angiotensin I is the rate-limiting step of the RAAS pathway.4 Angiotensin I is then converted to angiotensin II through angiotensin-converting enzyme (ACE). Angiotensin II, the primary effector molecule of the RAAS, has a number of biologic properties, including vasoconstriction, stimulation of the sympathetic nervous system, antinatriuresis, and increased aldosterone release.11 Aldosterone, an important but often overlooked component of the RAAS, seems to have an underrecognized role in patients with hypertension.12 The most well-known effect of aldosterone is the regulation of fluid and electrolyte homeostasis, mediated by the binding of aldosterone to cytosolic mineralocorticoid receptors in the distal convoluted tubule and cortical collecting duct.13 Additionally, aldosterone has nonepithelial effects (fibrosis, remodeling) that are mediated by mineralocorticoid receptors in multiple nonepithelial sites (vasculature, heart) and actions on the kidney (development of glomerulosclerosis, proteinuria) that may be independent of BP.13 The RAAS cascade allows for a number of potential therapeutic targets for the treatment of hypertension (Figure 4), such as ACE (ACE inhibitors), angiotensin type 1 receptors (angiotensin receptor blockers [ARBs]), renin (direct renin inhibitors [DRIs]), and aldosterone receptors (aldosterone receptor blockers). ACE inhibitors block the conversion of angiotensin I to angiotensin II, whereas ARBs block angiotensin II from binding to the type 1 receptor.

70

63.9

Patients, %

60 50 40 30 20

63.9

51.3

30.3

32.1

33.1

33.2

25.0 15.7

10 0 1999-2000

2001-2002

2003-2004

FIGURE 2. Age-adjusted control of hypertension in the United States.1 (White columns) All patients. (Black columns) Treated patients. (Gray columns) Treated patients with diabetes. © 2009 Lippincott Williams & Wilkins

BMI ≥ 30 kg/m2

Age 40-59

Age ≥ 60

Although effective, ACE inhibitors do not completely block the RAAS because there are alternative pathways to angiotensin biosynthesis in various tissues (heart, peripheral blood vessels, kidney, brain, and adrenal glands).14 –16 Angiotensin I can be produced by nonrenin enzymes, such as tonin or cathepsin, whereas the conversion from angiotensin I to angiotensin II can be catalyzed by enzymes, such as trypsin, cathepsin, and chymase.14 It is estimated that 40% of angiotensin II is formed by enzymes other than ACE.16 The increased levels of angiotensin II produced by this RAAS “escape” also promote aldosterone secretion.17 Similarly, ARBs incompletely inhibit RAAS because their longterm use results in increased levels of angiotensin I and II. This leads to inhibition of the negative feedback loop by which angiotensin II suppresses renin release, resulting in increased renin and increased plasma renin activity (Table 1).17,18 Further, neither ACE inhibitors nor ARBs produce complete inhibition of aldosterone, and aldosterone concentrations increase in many patients on long-term therapy.19 The observation that ACE inhibitors and ARBs are no more effective in specific populations, such as blacks, obese, or elderly, than other antihypertensive agents20 suggests that a more complete inhibition of RAAS activity has the potential to further improve clinical outcome. Additive approaches to achieve more complete RAAS inhibition have been shown to inhibit the effects of renin directly; an older approach that has recently seen a resurgence has been to antagonize the effects of aldosterone. Renin controls the rate-limiting step in the RAAS pathway, and, since its identification 50 years ago, it has been considered the ideal target for inhibiting RAAS activity.4 Aliskiren, the first and only currently available DRI, has been shown to be equivalent to ACE inhibitor or ARB treatment in BP-lowering efficacy when used as monotherapy.21–23 However, aliskiren provides additional BP-lowering effects when added to these same RAAS inhibitors.24,25 Whether these benefits translate into reductions in morbidity and mortality is being studied. Given the high prevalence of hyperaldosteronism in patients with hypertension, an aldosterone receptor antagonist is a reasonable approach to treating patients whose hypertension is not controlled on conventional antihypertensive therapy. The aldosterone antagonist spironolactone has been recommended as a fourth-line agent in the treatment of such patients.12 Another aldosterone antagonist is eplerenone. Unlike spironolactone, eplerenone has minimal activity at progesterone and androgen receptors and is selective for the aldosterone

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Basile

80 66.9

70

68.2

66.4 63.5

Patients, %

60

53.7

55.0

52.4

56.6†

48.3

50

35.4

40

28.9*

30

26.5*

20 10 0

Awareness

Treatment

Control, All Treated

Control, All Hypertensive

FIGURE 3. Awareness, treatment, and control of hypertension in various patient populations based on NHANES 2003–2004 data.1 *P ⬍ 0.05. †Estimate is unreliable because the coefficient of variation was greater than 0.3. NHANES, National Health and Nutrition Examination Survey. (White columns) Non-Hispanic white. (Black columns) Non-Hispanic black. (Gray columns) Mexican American.

receptor.26 Accordingly, the adverse effect profile of eplerenone is better than that of spironolactone. Treatment of Hypertension in Populations With a High Prevalence of Hypertension Blacks Although the prevalence and severity of hypertension are greater among black persons1 than among the general population, black persons often have a reduced response to antihypertensive agents—␤-blockers, ACE inhibitors, or ARBs—that exert particular effects on the RAAS.27 This may be because black persons are more likely to experience suppressed RAAS activity, as evidenced by low plasma renin activity, high salt sensitivity, and hypervolemia.28 Although ACE inhibitors and ARBs often must be administered with thiazide diuretics or calcium channel blockers for more effective BP reduction in black patients,28 their use should be based on the patient’s underlying vascular risk, not on the patient’s

skin color, because of the established benefits of ACE inhibitors and ARBs on organ protection.29,30 Aliskiren has demonstrated antihypertensive efficacy in black patients, though a pooled analysis of 7 randomized trials found that the effect seemed to be lower than that observed in Asian or white patients.31 As with other agents that antagonize RAAS, adding aliskiren to hydrochlorothiazide (HCTZ) improved the BP-lowering efficacy of HCTZ alone in black patients.31 Overall, aliskiren was well tolerated, and the incidence of related adverse events was comparable to that of placebo.31 Spironolactone has been effective in the treatment of black patients with resistant hypertension, regardless of the presence of primary aldosteronism.32 Among patients with low-renin hypertension (approximately one third were black), those receiving eplerenone 100 to 200 mg/d had significantly greater reductions in BP than those receiving losartan 50 to 100

Direct Renin Inhibitor

Neutralization of Plasma Renin Activity

Angiotensinogen Renin

Feedback Loop

Angiotensin I

Plasma Renin Activity

Angiotensin-Converting Enzyme

ACE Inhibitors

FIGURE 4. Renin-angiotensin-aldosterone system pathway and pharmacologic inhibition of the system. ACE, angiotensin-converting enzyme; AT1, angiotensin type 1 receptor.

Angiotensin II Angiotensin Receptor Blockers AT1 Receptor Aldosterone Aldosterone Receptor Blockers Aldosterone Receptor

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TABLE 1. Effects of antihypertensive agents on components of the RAAS pathway17,18 Drug class DRIs ACE inhibitors ARBs Aldosterone antagonists

Angiotensin I 2 1 1 1

Angiotensin II 2 2a 1 1

Renin concentration

Plasma renin activity

Aldosterone

1 1 1 1

2 1 1 1

2/3 2/3/1b 2/3c 1c

Adapted with permission from Staessen et al. Lancet 2006:368:1449 –56. 1, increased; 2, decreased; 3, neutral; ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; DRIs, direct renin inhibitors; RAAS, renin-angiotensin-aldosterone system. a Short-term dosing; with chronic dosing, returns to normal levels. b Variable (probably dose dependent). c Dose dependent.

mg/d (15.8/9.3 versus 10.1/6.7 mm Hg; P ⱕ 0.05) and were less likely to require add-on HCTZ for BP control (33% versus 56%; P ⫽ 0.003).33 The incidence of adverse events was similar between the groups.33 The most commonly reported adverse events were headache, upper respiratory tract infection, and dizziness; 2 cases of gynecomastia were reported in the eplerenone group. In another study, black patients treated with eplerenone 50 to 100 mg/d had significantly greater reductions in BP than those treated with losartan 50 to 100 mg/d (13.5/ 10.2 versus 5.3/6.0 mm Hg; P ⱕ 0.001).34 Active renin levels were significantly lower in black patients than in white patients (10.3 versus 13.8 mU/L; P ⬍ 0.001), but serum aldosterone levels were similar between the groups (6.8 versus 7.4 ng/dL; P ⫽ 0.25).34 No difference in the incidence of adverse events or laboratory parameters was reported between groups.34 No cases of gynecomastia or breast tenderness were reported for the eplerenone group. Older Individuals Hypertension increases progressively with advancing age. Normotensive individuals older than 55 have a 90% lifetime risk for hypertension,8 in part, because of age-related stiffness of large arteries and constriction of small arteries.35–37 Increasing age is also associated with endothelial dysfunction, which may be related to a decline in nitric oxide– dependent arterial vasodilation.35 In a pooled analysis, the antihypertensive efficacy of aliskiren was found to be independent of age.31 Across the dosage range of 75 to 600 mg/d, aliskiren produced similar BP reductions in patients 65 years and older compared with patients younger than 65 years.31 A double-blind trial in patients 65 years and older with hypertension (baseline BP 161/100 mm Hg) demonstrated that combination therapy with aliskiren 300 mg and valsartan 320 mg produced numerically greater reductions in BP than either agent alone [mean reductions were 19/12.6, 14.5/8.6, and 12.2/11 for combination, aliskiren, and valsartan groups, respectively; P ⬍ 0.05 for SBP combination versus valsartan and for diastolic BP (DBP) combination versus aliskiren].38 BP control rates were 43% for the combination group, 28% for aliskiren, and 25% for valsartan (P ⬍ 0.05 combination versus valsartan). Results from the Aliskiren for Geriatric Lowering of Systolic Hypertension study confirmed the efficacy and safety of aliskiren in 901 patients who were 65 years of age or older with systolic essential hypertension (baseline BP 157/86 mm Hg).39,40 In this double-blind trial, patients received monotherapy with aliskiren 150 mg or ramipril 5 mg for 4 weeks; the dose was then doubled in patients who were not at goal (SBP © 2009 Lippincott Williams & Wilkins

⬍140 mm Hg). After 12 weeks of therapy, if goal was still not achieved, HCTZ followed by amlodipine was added to the regimen. One third of the total population (32.5%) was at least 75 years of age. Aliskiren monotherapy was found to be noninferior to ramipril in reducing SBP from baseline at 12 weeks (mean reductions SBP 14.0 and 11.6 mm Hg in the aliskiren and ramipril groups, respectively; P ⬍ 0.0001; P ⫽ 0.0241 for superiority). Greater reductions were observed with an aliskiren-based regimen compared with a ramipril-based regimen at 36 weeks (mean reductions 20/8.2 and 18.1/7, respectively; P ⫽ 0.0747 for SBP and P ⫽ 0.0287 for DBP). Compared with ramipril, aliskiren required less frequent add-on therapy with HCTZ (46% versus 56%; P ⫽ 0.0048) or HCTZ plus amlodipine (12% versus 16%; P ⫽ 0.048) at 36 weeks. Both drugs were well tolerated with a low rate of adverse events reported in the groups. However, fewer patients reported cough with aliskiren-based therapy compared with ramiprilbased therapy (4% versus 13%, respectively).39,40 A randomized, double-blind trial in patients 50 years and older with systolic hypertension (baseline BP 166/86 mm Hg) showed that eplerenone (50 –200 mg/d) was as effective as amlodipine (5–10 mg/d) in reducing SBP.41 However, in patients with microalbuminuria, eplerenone reduced microalbuminuria to a greater extent than amlodipine (52% versus 10%, respectively, P ⫽ 0.04). Further, the quality of life analysis (SF-36 Health Survey) of this study found that eplerenone was much better tolerated than amlodipine, with regard to ankle swelling, weight gain, nocturia, increased urination, and shortness of breath.42 Obesity and Metabolic Syndrome Obesity and metabolic syndrome (combinations of abdominal obesity, glucose intolerance, hypertension, and dyslipidemia) are increasingly prevalent risk factors for cardiovascular disease and hypertension.27 In NHANES,1 obese persons had a more than 3-fold increased risk for hypertension than lean persons. For each 10% increase in weight, a 6.5–mm Hg increase in SBP is estimated.43,44 Increases in cardiac output, peripheral resistance, sympathetic activation, insulin resistance, and arterial stiffness may contribute to weight-related increases in BP.36,43 In a randomized, double-blind trial in obese patients (BMI ⱖ30 kg/m2) with mean sitting DBP ⱖ95 mm Hg and ⬍110 mm Hg, aliskiren 300 mg/d plus HCTZ 25 mg/d reduced BP significantly compared with HCTZ alone (15.8/11.9 versus 8.6/7.9 mm Hg; P ⬍ 0.0001) and was similar in efficacy to irbesartan/HCTZ (15.4/11.3 mm Hg) or amlodipine/HCTZ (13.6/10.3 mm Hg) after 8 weeks of treatment.45 The incidence of adverse effects reported across groups was similar, but a

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higher proportion of patients in the amlodipine/HCTZ group had peripheral edema (0.8% in aliskiren/HCTZ; 0.8% in irbesartan/HCTZ; 1.6% in HCTZ; and 11.1% in amlodipine/ HCTZ).45 Post hoc analysis found that among the subset of patients with the most severe degree of obesity (BMI ⱖ40 kg/m2), aliskiren/HCTZ-treated patients were significantly more likely to reach target BP (68.8%) than those receiving HCTZ alone (16.7%; P ⫽ 0.004) or amlodipine/HCTZ (43.8%; P ⬍ 0.05), and a higher number reached target BP than those treated with irbesartan/HCTZ (50.0%).46 A pooled analysis of 10 randomized, double-blind trials found that aliskiren 150 or 300 mg/d produced similar BP reductions and BP control rates in patients with or without metabolic syndrome, with the exception of slightly greater reductions in SBP with aliskiren 300 mg/d in patients without metabolic syndrome than in those with metabolic syndrome (16.2 versus 14.8 mm Hg, respectively).47 No studies focusing on the use of aldosterone antagonists in obese patients or patients with metabolic syndrome have been published. Diabetes and Chronic Kidney Disease Patients with diabetes and chronic kidney disease experience RAAS dysregulation.4,48 Thus, it has been suggested by some clinicians that effective antihypertensive therapy with RAAS modulators may be the single most important therapy for these patients.49 Overwhelming evidence has shown that ACE inhibitors and/or ARBs are effective for reducing diabetic nephropathy and slowing the progression of renal disease, and evidence-based guidelines support their use in these populations.27,50,51 A large, randomized, double-blind trial, including 837 hypertensive patients with type 1 or type 2 diabetes, compared aliskiren 150 mg, ramipril 5 mg, and a combination of both administered once daily for 4 weeks, followed by forced titration to double dose for another 4 weeks.24 Mean sitting SBP/DBP reductions were 14.7/11.3, 12.0/10.7, and 16.6/12.8 mm Hg for aliskiren, ramipril, and aliskiren/ramipril combination therapy, respectively. Aliskiren and aliskiren/ramipril combination therapy significantly reduced SBP compared with ramipril monotherapy (P ⬍ 0.05 for monotherapy; P ⬍ 0.0001 for combination therapy). Responder rates for aliskiren monotherapy (73.1%) and aliskiren/ramipril (74.1%) were also significantly greater than with ramipril alone (65.8%; P ⬍ 0.05 for both).24 Combination therapy with aliskiren and ramipril was well tolerated. Coughing was reported by 4.7% of patients receiving ramipril, 2.1% receiving aliskiren, and 1.8% receiving aliskiren/ramipril combination therapy.24 Data on the efficacy of DRIs in diabetic nephropathy are beginning to emerge. Results from the Aliskiren in the Evaluation of Proteinuria in Diabetes study demonstrated a significant reduction of 20% in mean urinary albumin-to-creatinine ratio in patients who received aliskiren in addition to treatment with the maximum recommended dose of losartan compared with losartan alone in hypertensive patients with type 2 diabetes and nephropathy.52 However, Aliskiren in the Evaluation of Proteinuria in Diabetes study used a surrogate marker for end-stage renal disease for its primary end point, and this cannot be directly translated into reduction of clinical events. Therefore, the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Disease Endpoints study (NCT00549757) is currently being conducted. This long-term outcomes trial will compare the efficacy and safety of aliskiren versus placebo when added to a conventional therapy regimen that includes an ACE inhibitor or ARB in the reduction of cardiovascular and

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renal morbidity and mortality in patients with type 2 diabetes, nephropathy, and those with a history of cardiovascular disease. Results from this trial are expected in 2012. The rationale for the use of aldosterone antagonists in patients with type 2 diabetes and early nephropathy was previously demonstrated in a small trial that showed a beneficial effect on albuminuria in patients with aldosterone escape who were receiving an ACE inhibitor.53 In an uncontrolled pilot study that evaluated the short-term (8 weeks) administration of spironolactone when added to ACE inhibitor or ARB therapy, the aldosterone antagonist reduced proteinuria, and the degree of reduction in proteinuria was significantly correlated with baseline aldosterone level (r ⫽ 0.70; P ⬍ 0.0001).54 A randomized, double-blind, crossover study in type 2 diabetics with nephropathy found that the addition of spironolactone 25 mg once daily to conventional antihypertensive treatment (diuretics and maximally recommended ACE inhibitor or ARB therapy) significantly reduced proteinuria by 33% (95% CI 25– 41; P ⬍ 0.001), and ambulatory SBP and DBP by 6 mg and 4 mg, respectively (P ⬍ 0.001 for both).55 The addition of spironolactone 25 mg once daily to usual antihypertensive therapy also resulted in similar reductions in proteinuria by 30% (95% CI 17– 41; P ⬍ 0.001) in patients with type 1 diabetes.56 In another study, spironolactone 25 mg once daily significantly reduced proteinuria when added to a stable dose of trandolapril that was independent of BP reduction in patients with chronic renal disease and proteinuria of more than 0.5 g/d.57 The effect on reduction in proteinuria was significantly greater in patients with diabetes than those without diabetes. In a placebocontrolled, double-blind trial in patients with type 2 diabetes and macroalbuminuria, the addition of spironolactone 25 to 50 mg/d to ACE inhibitor or ARB therapy reduced albuminuria by 40.6% and BP by a mean of 7/3 mm Hg compared with placebo.58 However, hyperkalemia has been reported with the use of spironolactone in patients with diabetic nephropathy and other types of chronic kidney disease.55–58 In patients with type 2 diabetes and albuminuria, the addition of eplerenone to enalapril (with or without concomitant use of amlodipine) was associated with a significant reduction in albuminuria of 41% and 48% in the eplerenone 50 and 100 mg groups, respectively (P ⬍ 0.001 for both versus placebo) without resulting in increases in hyperkalemia.59 Resistant Hypertension Many of the aforementioned patient groups also have resistant hypertension, which is defined as a BP that remains above goal, despite the use of 3 agents from different classes.3 The observation that primary aldosteronism is relatively common (incidence up to 20%) in patients with resistant hypertension supports the use of aldosterone antagonists in this population.12,60 – 62 The largest study evaluating spironolactone in hypertensive patients who were unresponsive to standard therapies was the Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm trial. Among patients with hypertension uncontrolled by a mean of 3 antihypertensive agents, adding once-daily spironolactone (median dose 25 mg) produced BP reductions of 21.9/9.5 mm Hg after a median duration of 1.3 years. Efficacy was generally unaffected by age, sex, smoking, or diabetes status.63 The most frequently reported adverse effects were gynecomastia (6%), which resulted in 3% of discontinuations, and biochemical abnormalities (2%), which were mostly attributed to hyperkalemia.63 DRIs have not been studied in patients with resistant hypertension. Volume 337, Number 6, June 2009

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CONCLUSIONS Control of BP through pharmacologic intervention is important for decreasing or preventing complications associated with hypertension. The prevalence of hypertension is greater in certain populations (black, elderly, or obese patients; patients with metabolic syndrome, frank diabetes, or chronic kidney disease). The RAAS plays a pivotal role in the development of hypertension and organ damage, and the benefits of RAAS inhibitors, namely ACE inhibitors and ARB therapy, have been well recognized. Recent therapeutic advances, such as the development of DRIs and aldosterone receptor antagonists, offer the potential for maximizing RAAS blockade, especially when added to conventional therapy. Data regarding the use of DRIs in diabetes and chronic renal disease show promise, whereas aldosterone antagonists have demonstrated particular benefit in patients with resistant hypertension.

15. Carey RM, Siragy HM. Newly recognized components of the reninangiotensin system: potential roles in cardiovascular and renal regulation. Endocr Rev 2003;24:261–71. 16. Hollenberg NK, Fisher NDL, Price DA. Pathways for angiotensin II generation in intact human tissue: evidence from comparative pharmacological interruption of the renin system. Hypertension 1998;32:387–92. 17. Staessen JA, Li Y, Richart T. Oral renin inhibitors. Lancet 2006;368: 1449 –56. 18. Wenzel U. Aldosterone and progression of renal disease. Curr Opin Nephrol Hypertens 2008;17:44 –50. 19. Lakkis J, Lu WX, Weir MR. RAAS escape: a real clinical entity that may be important in the progression of cardiovascular and renal disease. Curr Hypertens Rep 2003;5:408 –17. 20. Ibrahim MM. RAS inhibition in hypertension. J Hum Hypertens 2006;20:101– 8.

ACKNOWLEDGMENT Editorial support was provided by ApotheCom and funded by Novartis Pharmaceuticals Corp.

21. Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005;111:1012– 8.

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Volume 337, Number 6, June 2009