Aliskiren: Renin inhibitor for hypertension management

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Clinical Therapeutics/Volume 30, Number 1, 2008

New Drug

Aliskiren: Renin Inhibitor for Hypertension Management Judy W.M. Cheng, BS, PharmD, MPH, FCCP, BCPS Massachusetts College of Pharmacy and Health Sciences and Brigham and Women’s Hospital, Boston, Massachusetts ABSTRACT Background: The renin-angiotensin-aldosterone system (RAAS) has long been recognized to play a significant role in hypertension pathophysiology. Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes. Aliskiren is the first of a new class of antihypertensive agents known as renin inhibitors. Objective: The goal of this article was to discuss the clinical pharmacology of aliskiren and its use in the management of hypertension, as well as potential uses in other cardiovascular disorders. Methods: Peer-reviewed articles and abstracts were identified from the MEDLINE and Current Contents databases (both 1966–October 1, 2007) using the search terms aliskiren, drug interaction, pharmacokinetics, and pharmacology. Citations from available articles were reviewed for additional references. Abstracts presented at recent professional meetings were also examined. Results: Nine published clinical studies have evaluated the effect of aliskiren in lowering blood pressure in hypertensive patients, either alone or in combination with other antihypertensive agents. This review summarizes those studies. Patients treated with aliskiren had significantly lower blood pressure compared with patients with mild to moderate hypertension (systolic blood pressure [SBP] 140–180 mm Hg and diastolic blood pressure [DBP] 95–110 mm Hg) who received placebo. Aliskiren in doses of 75 to 300 mg daily produced reductions of SBP (–5.3 to –15.8 mm Hg) and DBP (–5.8 to –12.3 mm Hg); placebo produced reductions of SBP that ranged from –2.85 to –10.0 mm Hg and DBP reductions from –3.26 to –8.6 mm Hg (P < 0.05 in all studies between aliskiren and placebo). Aliskiren’s blood pressure–lowering effect at doses of 75 to 300 mg daily was comparable to irbesartan 150 mg daily and valsartan 80 to 360 mg daily alone. January 2008

When aliskiren was added to ramipril, hydrochlorothiazide, amlodipine, irbesartan, or valsartan, significant additive blood pressure–lowering effects were reported (P < 0.05 in all clinical trials). The total incidence of adverse events was similar to placebo and other comparative agents, including irbesartan, valsartan, losartan, ramipril, and hydrochlorothiazide. The overall adverse-event rates were 22%, 35% to 52%, 25% to 52%, 34% to 55%, and 33% to 52% for aliskiren 37.5, 75, 150, 300, and 600 mg, respectively. The most commonly reported adverse events included headache, dizziness, and fatigue. Studies with cardiovascular outcomes as end points have not been performed with aliskiren. Conclusions: Aliskiren is an effective alternative agent for blood pressure management. Before aliskiren can be recommended as a routine first-line agent, however, clinical studies must explore if the blood pressure–lowering effect will translate into improvement in cardiovascular outcomes. (Clin Ther. 2008;30: 31–47) © 2008 Excerpta Medica Inc. Key words: aliskiren, systolic blood pressure, diastolic blood pressure, cardiovascular outcomes.

INTRODUCTION High blood pressure is a prevalent risk factor for cardiovascular disease, affecting >72 million people in the United States and >1 billion people worldwide.1 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends a blood pressure treatment goal of <140/90 mm Hg for most Accepted for publication November 5, 2007. doi:10.1016/j.clinthera.2008.01.011 0149-2918/$32.00 © 2008 Excerpta Medica Inc. All rights reserved.

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Clinical Therapeutics patients and <130/80 mm Hg for patients with diabetes mellitus (DM) or kidney disease.2 Despite the effort of the JNC 7 to increase the awareness and treatment of hypertension in the United States, only 34% of patients have blood pressure that is adequately controlled.2 Choosing the appropriate medications for individual patients and adherence to these regimens are among the most important contributing factors to the success of hypertension control. Of all the different pharmacologic agents that the JNC 7 guidelines recommended for hypertension management, medications that work by inhibiting the renin-angiotensin-aldosterone system (RAAS) are among some of the most commonly prescribed in the United States; these include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and aldosterone antagonists.3 Not only do these agents help control blood pressure, they have also been found to reduce cardiovascular events in some disease states.2 ACE inhibitors and ARBs have been shown to reduce mortality and recurrent cardiovascular events in patients with heart failure, myocardial infarction, and previous stroke.4–6 In patients with DM or kidney disease, ACE inhibitors and ARBs also reportedly preserve kidney function in addition to improving cardiovascular outcomes.7 Aldosterone antagonists have been found to reduce mortality in patients with left ventricular dysfunction as well as myocardial infarction.8 Currently, there are no published data on the effect of aliskiren on these outcomes. On March 6, 2007, the US Food and Drug Administration approved aliskiren,* the first of a new class of antihypertensive agents known as renin inhibitors, for hypertension management.9 It becomes the fourth class of pharmacologic agents that modify the function of RAAS. The goal of this article was to discuss the clinical pharmacology of aliskiren and its use in the management of hypertension, as well as potential uses in other cardiovascular disorders.

METHODS Peer-reviewed articles and abstracts (English-language only) were identified from the MEDLINE and Current Contents databases (both 1966–October 1, 2007) using the search terms aliskiren, drug interaction, *Trademark: Tekturna® (Novartis Pharmaceuticals Corporation, East Hanover, New Jersey).

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pharmacokinetics, and pharmacology. Citations from available articles were reviewed for additional references. Given the fact that aliskiren was only approved in 2007, some pertinent clinical studies may not have been published. Therefore, abstracts of unpublished clinical studies presented at professional meetings in 2006 and 2007 were also examined.

PHYSIOLOGY OF THE RENIN-ANGIOTENSINALDOSTERONE SYSTEM AND HYPERTENSION The RAAS plays a significant role in the pathophysiology of hypertension. The juxtaglomerular cells in the afferent renal arterioles secrete renin in response to low plasma volume, reduced renal perfusion, or increased sympathetic central nervous system activity.10 Renin acts as a protease enzyme that catalyzes the conversion of angiotensinogen to angiotensin I, which is subsequently converted to angiotensin II by ACE. Angiotensin II induces adrenal secretion of aldosterone, which is a mineralocorticoid that leads to sodium and fluid retention, thus increasing blood pressure.10 Angiotensin II also has a direct vasoconstrictive effect, which increases blood pressure, and promotes inflammation and remodeling of the cardiovascular system, which leads to thrombosis or left ventricular hypertrophy.11 Renin conversion of angiotensinogen to angiotensin I is the rate-limiting step in angiotensin II formation. Renin is therefore the primary determinant of RAAS activity.11 ACE inhibitors hinder the systemic effect of angiotensin II by inhibiting ACE, which reduces the conversion of angiotensin I to angiotensin II.12 ARBs directly inhibit the binding of angiotensin II to the receptor.13 Aldosterone antagonists inhibit the action of the excessive aldosterone produced due to increases in angiotensin II.14 However, both ACE inhibitors and ARBs can lead to increases in plasma renin activity. With ACE inhibitors, the angiotensin I level increases and may lead to accessory (ie, non-ACE pathways) production of angiotensin II.15,16 These pathways convert angiotensin I to angiotensin II through alternative enzymes such as chymase and chymotrypsin-like angiotensin-generating enzyme.17,18 With ARBs, angiotensin II levels will increase to compete for receptor bindings. Such increases in angiotensin II levels may also continue to stimulate release of aldosterone from the adrenal gland.17 Research has attempted to improve RAAS inhibition through the combination use of ACE inhibitors Volume 30 Number 1

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J.W.M. Cheng and ARBs.19 Direct renin inhibitors may offer more advantages than the combination of an ACE inhibitor and ARB by directly inhibiting the RAAS at its ratelimiting step and preventing compensatory RAAS activation, thus potentially reducing non-ACE production of angiotensin II.20

CLINICAL PHARMACOLOGY OF ALISKIREN Mechanism of Action Aliskiren is a direct inhibitor of renin. It decreases plasma renin activity, thus decreasing the conversion of angiotensinogen to angiotensin I. It is not known whether aliskiren affects other RAAS components.21 Aliskiren’s inhibitory effect of renin is potent and highly specific (50% inhibitory concentration, 0.6 mmol/L).21 Unlike other previously synthesized but not marketed renin inhibitors (eg, remikiren, enalkiren, zankiren), aliskiren exhibits oral bioavailability due to its low molecular weight (609.8 Da) and nonpeptide structure, making it more resistant to gastrointestinal enzyme disintegration.22 The inhibition of renin by aliskiren is associated with a reduction in circulating levels of angiotensin I and II, with a resultant increase in plasma renin concentration. However, despite this elevated renin concentration, aliskiren effectively reduces functional plasma renin activity by binding to renin with high affinity, preventing it from converting angiotensinogen to angiotensin I (indirectly measured by using plasma angiotensin I concentrations) throughout the 24-hour dosing interval.21,23 The reduction in plasma renin activity, which ranges from ~50% to 80%, is dose related but does not correlate with blood pressure reduction.23,24

Pharmacokinetics Although aliskiren exhibits oral bioavailability compared with other previously synthesized renin inhibitors, it is still poorly absorbed (oral bioavailability, ~2.5%).25 In 9 healthy volunteers aged 20 to 34 years, after administration of oral aliskiren 40 to 640 mg daily, the plasma concentration exhibited dose-dependent increases, with peak concentrations achieved after 3 to 6 hours of administration.23 When administered with a high-fat meal, mean AUC and the maximum concentration of aliskiren were decreased by 71% and 85%, respectively.25 However, this does not affect the inhibition of plasma renin activity.23 Aliskiren is 50% protein bound, and the apparent volume of distribution is 135 L.26 January 2008

The main elimination route of aliskiren is via biliary excretion (91%) as unmetabolized drug. Approximately 25% of the absorbed aliskiren is eliminated in the urine unchanged as the parent compound. Aliskiren is also metabolized by cytochrome P450 (CYP) 3A4 enzymes, but the exact extent of metabolism is unknown.22,23,26 Aliskiren reportedly does not inhibit CYP isozymes at concentrations up to 50 to 100 times maximum concentrations measured in clinical trials.26 The elimination t1/2 of aliskiren averaged 24 hours (20–45 hours) in healthy volunteers as well as in patients with DM.27 Plasma steady-state concentrations are therefore achieved in ~5 to 8 days (5 times the half-life). This relatively long half-life makes aliskiren suitable for QD dosing.

Special Populations An open-label, multicenter study compared the pharmacokinetic profile of aliskiren in 29 elderly patients (aged >65 years) and 28 younger healthy subjects (age range, 18–45 years).28 After administration of a single 300-mg oral dose, AUC was 57% higher in the older patients than in the younger subjects (P = 0.008). Although not statistically significant, the peak concentration was 28% higher in the elderly patients than in the younger subjects.28 Aliskiren was well tolerated in all individuals. The blood pressure–lowering response did not differ significantly between the 2 groups. Therefore, no dosage adjustment is required for elderly patients taking aliskiren. The pharmacokinetics of aliskiren have not been investigated in patients aged <18 years. The pharmacokinetic profile of aliskiren has been investigated in 19 Japanese patients compared with results from 19 white patients aged 20 to 45 years.29 After administration of one 300-mg oral dose of aliskiren, there was no notable difference in AUC, peak plasma concentration, or t1/2 of aliskiren among these patients. Therefore, dosing strategies in these patients are similar. It has also been reported that the pharmacokinetic differences between blacks and whites are minimal.25 In patients with varying degrees of renal dysfunction, the AUC and peak plasma concentration of aliskiren did not suggest correlation with the severity of renal impairment.25,30 In patients with mild (ChildPugh Clinical Assessment score, 5–6) to severe (ChildPugh Clinical Assessment score, 10–15) hepatic impairment, no significant differences were observed 33

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Clinical Therapeutics among all the pharmacokinetic parameters of aliskiren (AUC and peak plasma concentration) compared with healthy volunteers.31 Therefore, dosage adjustment is not required for patients with renal or hepatic dysfunction. As with ACE inhibitors and ARBs, aliskiren is designated pregnancy category C in the first trimester and category D in the second and third trimesters.25 Drugs that directly affect the RAAS can cause fetal and neonatal morbidity and death when administered to pregnant women.32 Use of aliskiren has not been evaluated in pregnant women. Although reproductive studies of aliskiren did not reveal teratogenicity at oral doses ≤600 mg/kg per day in pregnant rats or ≤100 mg/kg per day in pregnant rabbits, fetal birth weight was adversely affected in rabbits at the 50-mg/kg daily dose.25 Aliskiren was found in the placenta, as well as the amniotic fluid and fetuses, of pregnant rabbits.25

Pharmacodynamics In a double-blind, 3-way crossover study, 18 male normotensive healthy volunteers aged 20 to 35 years were randomized to enalapril 20 mg or placebo and then given 2 escalating oral doses of aliskiren (either 40 and 80 mg or 160 and 640 mg QD).23 Each subject participated in the three 8-day study periods, which were separated by 6-day washout periods. Angiotensin II levels were significantly decreased from baseline to 6 hours by aliskiren at all doses except the 40-mg dose (P < 0.05). Aliskiren also decreased plasma renin activity and plasma concentrations of angiotensin I in a dose-dependent fashion. The percent inhibition of angiotensin II by aliskiren at doses of 160 or 640 mg were 56% and 76%, respectively; the percent inhibition of angiotensin II by enalapril 20 mg was 57%. Plasma renin activity and angiotensin I inhibition paralleled the changes in angiotensin II after aliskiren administration. Conversely, plasma renin activity and angiotensin I levels were increased by enalapril 15-fold compared with baseline (P < 0.05). All regimens were well tolerated by the subjects. Blood pressure and heart rate were unchanged compared with baseline in both the aliskiren and enalapril groups. Aliskiren was thus associated with a reduction in angiotensin II plasma concentrations without a reflex increase in plasma renin activity and angiotensin I levels in this study.23 In a small pilot study with a randomized, 4-way crossover design, Azizi et al24 administered single 34

doses of oral aliskiren 300 mg, oral valsartan 160 mg, a combination of oral aliskiren 150 mg and valsartan 80 mg, or placebo to 12 male normotensive volunteers (age range, 20–35 years). Aliskiren 300 mg completely inhibited plasma renin activity within 1 hour of intake, and this inhibition persisted for 48 hours (P < 0.05 compared with placebo at all time points). Conversely, plasma renin activity increased within 4 hours of valsartan 160-mg administration and was still elevated 24 and 48 hours after dosing (P < 0.05 vs placebo at all time points). The effect of inhibiting plasma renin activity by the combined regimen was similar to that of aliskiren 300 mg and significantly greater than valsartan 160 mg (P < 0.05). These findings suggest that, at lower doses, renin inhibitors and ARBs might have synergistic effects on the renin system. Aliskiren blunted the valsartan-induced increase in plasma renin activity and plasma concentration of angiotensin I and II. The active drugs were associated with a reduction in mean arterial pressure at 4 hours after administration by ~5 to 7 mm Hg, but these blood pressure responses were no longer apparent at 24 hours.24 Moore et al33 evaluated renin gene polymorphisms and haplotypes in blood pressure responses to aliskiren. It has been reported that the presence of a –5312T allele rather than a –5312C allele at a distal nucleotide enhancer region can activate the human renin promoter and increase rates of renin gene transcription by 45%, thus increasing susceptibility to hypertension.34 Three hundred forty-five patients aged between 21 and 70 years, with systolic blood pressure (SBP) >140 mm Hg, were randomized to receive aliskiren 37.5, 75, 150, or 300 mg daily or losartan 100 mg daily for 4 weeks. Patients provided additional blood samples for genotyping. Patients with the –5312T allele had significantly higher baseline blood pressure than those with the –5312C allele (SBP 2.5 mm Hg higher, diastolic blood pressure [DBP] 2.4 mm Hg higher; P < 0.01). Nighttime blood pressure reductions with losartan were significantly greater in the –5312T allele carriers than in the –5312C allele carriers (SBP/DBP, –12.9/–7.9 vs –7.1/–4.2 mm Hg; P < 0.03 for treatment and genotype interaction). For aliskiren 150 and 300 mg, lesser reductions were observed in the –5312T allele carriers than in the –5312C allele carriers (SBP/DBP, –5.4/–4.1 vs –10.1/–6.5 mm Hg; P < 0.01 for treatment and genotype interaction). The investigators postulated that the mechanism of these Volume 30 Number 1

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J.W.M. Cheng observed differences may be due to the high affinity binding of aliskiren to the elevated tissue renin in –5312T allele carriers, thus leading to lesser vascular effect and lower blood pressure reduction. Further studies must be performed to confirm the mechanism. Nevertheless, the investigators suggested that genotyping at this locus may help in identifying the risk of hypertension and aid in choosing optimal pharmacotherapy for individual patients.

Drug Interactions Most drug-interaction studies performed with aliskiren examined the interaction between the new renin inhibitor and common medications that patients may receive for hypertension-associated comorbidities. Four separate studies investigated the pharmacokinetic interaction between single oral doses of aliskiren and lovastatin, atenolol, celecoxib, or cimetidine.35 All studies enrolled healthy male volunteers aged 18 to 45 years. In 3 studies, a 3-period crossover design was used. Subjects (n = 15 in each study) were given 1 dose of aliskiren 150 mg alone, the test drug alone (lovastatin 40 mg, atenolol 100 mg, or celecoxib 200 mg), or both drugs in combination. In the cimetidine study (n = 12), aliskiren 150 mg was administered alone or concomitantly with cimetidine 800 mg using a crossover design. Mean AUC, peak plasma concentration, and t1/2 of aliskiren were not affected by coadministration of lovastatin, atenolol, or celecoxib. When coadministered with cimetidine, there was a nonsignificant increase in aliskiren systemic availability (aliskiren mean AUC, maximum plasma concentration, and t1/2 increased by 17%, 19%, and 15%, respectively). Aliskiren coadministration therefore had no significant effect on the pharmacokinetic profiles of lovastatin, atenolol, celecoxib, or cimetidine. Similarly, another 4 studies investigated the pharmacokinetic interactions between aliskiren 300 mg and amlodipine 10 mg (n = 18; mean age, 33.7 years), valsartan 320 mg (n = 18; mean age, 31.7 years), hydrochlorothiazide (HCTZ) 25 mg (n = 22; mean age, 28.1 years), and ramipril 10 mg (n = 17; mean age, 26.6 years) in healthy volunteers.36 In each study, subjects received multiple QD doses of aliskiren and the test antihypertensive drug alone or in combination in 2 dosing periods separated by a drug-free washout period. In period 1, subjects received QD treatment with the test antihypertensive drug for 14 days, followed January 2008

by a washout period of 7 days. In period 2, subjects received QD oral doses of aliskiren 300 mg for 14 days, followed by aliskiren coadministered with the test antihypertensive drug for 14 days. At steady state, relatively small but significant changes in exposure to aliskiren were observed when aliskiren was coadministered with amlodipine (AUC increased by 29%; P = 0.032), ramipril (maximum plasma concentration increased by 31%; P = 0.043), valsartan (AUC decreased by 26%; P = 0.002), and HCTZ (maximum plasma concentration decreased by 22%; P = 0.039). Conversely, coadministration with aliskiren also resulted in small changes in exposure to ramipril (AUC increased by 22%; P = 0.002), valsartan (AUC decreased by 14%; P = 0.062), and HCTZ (AUC decreased by 10% and maximum plasma concentration by 26%; both P < 0.001). None of these observed changes were considered clinically relevant by the investigators. Therefore, it was concluded that aliskiren is generally well tolerated when administered in combination with amlodipine, valsartan, HCTZ, or ramipril. The interaction between aliskiren and warfarin has also been explored. In a single-blind, placebocontrolled, randomized, 2-period crossover study, 13 healthy male and 2 female subjects (mean age, 29 years) received QD doses of aliskiren (150 mg) or placebo for 11 days, with a single dose of warfarin (25 mg) given on day 8 of each treatment period, separated by a washout period of at least 21 days.37 Aliskiren treatment had no effect on the blood coagulation parameters (prothrombin time, international normalized ratio, and activated partial thromboplastin time) or pharmacokinetic parameters (AUC, maximum plasma concentration, and t1/2) of warfarin. Because aliskiren is partly metabolized by the CYP3A4 enzyme,22,23,26 potential interactions with medications that induce or inhibit the activity of CYP3A4 may occur. Coadministration of 200 mg BID of ketoconazole (a potent CYP3A4 enzyme inhibitor) with aliskiren (dose not specified) reportedly increased plasma levels of aliskiren by ~80% (P value not reported).25 The clinical significance of this interaction has not been explored. When ketoconazole and aliskiren are administered concomitantly, lower doses of aliskiren should be initiated first, and blood pressure–lowering response should be monitored closely. Alternatively, a triazole antifungal not metabolized by CYP3A4 (eg, fluconazole) may be used instead of ketoconazole. 35

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Clinical Therapeutics

CLINICAL STUDIES OF ALISKIREN To date, 9 published clinical trials have evaluated the effect of aliskiren in lowering blood pressure in hypertensive patients, either alone or in combination with other antihypertensive agents (Table I).38–46 Stanton et al38 performed a randomized, double-blind, activecontrolled trial evaluating the blood pressure–lowering efficacy and tolerability effects of aliskiren. One hundred ninety-seven patients (130 male, 67 female; age range, 21–70 years) with mean SBP >140 mm Hg were randomly assigned to receive 37.5, 75, 150, or 300 mg of aliskiren or 100 mg of losartan daily for 4 weeks. Patients who were unable to withdraw from current antihypertensive medications or if they had secondary hypertension, malignant hypertension (SBP >180 mm Hg or DBP >110 mm Hg), DM, coronary artery disease, or any medical condition that might affect the pharmacokinetics of aliskiren were excluded. No other blood pressure medications were allowed in the study. Dose-dependent reductions in daytime ambulatory SBP (mean change, –0.4, –5.3, –8.0, and –11.0 mm Hg [P < 0.001, dose-dependent treatment effect]) and in plasma renin activity (median change, –55%, –60%, –77%, and –83% [P < 0.001, dosedependent treatment effect]) were observed with 37.5-, 75-, 150-, and 300-mg aliskiren, respectively. The change in daytime SBP with 100-mg losartan (–10.9 mm Hg) was significantly greater than with aliskiren 37.5 mg (P < 0.05) but not significantly different from the changes seen with 75-, 150-, or 300-mg aliskiren. Aliskiren was well tolerated at all doses studied. Twentyseven percent of patients reported at least 1 adverse event. The most commonly reported adverse events included fatigue or weakness, gastrointestinal disorders, and headache. This study found that aliskiren was an effective and well-tolerated alternative for hypertension management. Kushiro et al39 evaluated the antihypertensive efficacy and tolerability of aliskiren in 455 Japanese patients (330 males, 125 females; age range, 20–80 years) with mean sitting DBP of 95 to 110 mm Hg. Patients were excluded who were pregnant or who had secondary hypertension; severe hypertension (SBP >180 mm Hg or DBP >110 mm Hg); DM; serious cardiac, hepatic, renal, or cerebrovascular disease; or a history of pancreatitis, malignant tumor, autoimmune diseases, anemia, gout, or hyperthyroidism. Patients were randomized to receive QD aliskiren 75, 150, or 300 mg or placebo for 8 weeks. No other concurrent anti36

hypertensive agents were allowed during the study period. Aliskiren and placebo produced dose-dependent reductions in mean SBP (–8.57, –8.72, –14.09, and –2.85 mm Hg, respectively [P < 0.001, dose-dependent effect]) and DBP (–7.22, –7.75, –10.72, and –3.26 mm Hg, respectively [P < 0.001, dose-dependent effect]). The changes with aliskiren were significantly different at all doses compared with placebo (P < 0.001, all doses). Aliskiren was well tolerated at all doses, and the incidence of adverse events reported was similar to that of placebo (53%–55% for aliskiren and 50% for placebo). The most commonly reported adverse events were nasopharyngitis (17.7%–20.9%, depending on dose), headache (2.6%–5.3%, depending on dose), and laryngopharyngitis (0.9%–1.7%, depending on dose). This study found that aliskiren was an effective alternative antihypertensive agent for these Japanese patients. Gradman et al40 performed a randomized, doubleblind study evaluating the antihypertensive effect of aliskiren. A total of 652 patients (325 males, 327 females; aged >18 years) with mean DBP ≥95 mm Hg but ≤110 mm Hg were randomized to oral aliskiren (150, 300, or 600 mg daily), irbesartan (150 mg daily), or placebo for 8 weeks. Patients were excluded if they had severe hypertension (SBP >180 mm Hg or DBP >110 mm Hg), secondary hypertension, DM, history of cardiovascular disease, malignancy or other lifethreatening disease, or any medical condition that might affect the pharmacokinetic profile of aliskiren. No other concurrent antihypertensive agents were allowed during the study period. Aliskiren 150, 300, and 600 mg effectively lowered both trough mean sitting DBP and SBP (P < 0.001 vs placebo for both variables). The mean reductions in DBP were 9.3, 11.8, and 11.5 mm Hg for the 3 doses, respectively, versus a 6.3–mm Hg increase in the placebo group. The mean reductions in SBP were 11.4, 15.8, and 15.7 mm Hg, respectively, versus 5.3 mm Hg for placebo. The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg. However, aliskiren 300 and 600 mg lowered mean sitting DBP significantly more than irbesartan 150 mg (P < 0.05). It was concluded that QD oral treatment with aliskiren lowers blood pressure effectively, with a tolerability profile comparable to that of irbesartan and placebo. The most commonly reported adverse events were headache (7%), dizziness (5%), and diarrhea (4%). In patients with mild to moderate hypertension, aliskiren Volume 30 Number 1

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O’Brien et al41

R, open- 18–80 label, Years controlled

Gradman R, DB, >18 et al40 placebo Years controlled

67

652

SBP, 140– 180

SBP, <180, DBP ≥95 but ≤110 8 Weeks

8 Weeks

ALK 75 or 150 mg 3 Weeks daily alone or in combination with HCTZ 25 mg daily, RAM 5 mg daily, or IRB 150 mg daily

ALK 150, 300, or 600 mg daily or IRB 150 mg daily or placebo

DBP, ALK 75, 150, or 95–110 300 mg daily or placebo

R, DB, 20–80 455 placebo Years controlled

Kushiro et al39

Duration

ALK 37.5, 75, 150, 4 Weeks or 300 mg daily or LOS 100 mg daily

SBP, >140

Regimen

Daytime ALK 150 mg: –5.8 vs ALK 150 mg + HCTZ: –8.8¶ RAM: –5.9 vs ALK 75 mg + RAM: –8.1 vs ALK 150 mg + RAM: –8.7¶

ALK 150 mg: –9.3‡ ALK 300 mg: –11.8‡㛳 ALK 600 mg: –11.5‡㛳 IRB: –8.9‡ Placebo: 6.3

ALK 75 mg: –7.22‡ ALK 150 mg: –7.75‡ ALK 300 mg: –10.72‡ Placebo: –3.26

NA

Daytime ALK 150 mg: –10.6 vs ALK 150 mg + HCTZ: –18.4¶ RAM: –6.1 vs ALK 75 mg + RAM: –10.5¶ vs ALK 150 mg + RAM: –14.0¶

ALK 150 mg: –11.4§ ALK 300 mg: –15.8§ ALK 600 mg: –15.7§ IRB: –12.5 Placebo: –5.3

ALK 75 mg: –8.57§ ALK 150 mg: –8.72§ ALK 300 mg: –14.09§ Placebo: –2.85

ALK 37.5 mg: –0.4* ALK 75 mg: –5.3* ALK 150 mg: –8.0* ALK 300 mg: –11.0* LOS: –10.9†

SBP Reduction, mm Hg

(continued)

No significant difference among groups ALK + HCTZ: 11 events ALK + RAM: 25 events ALK + IRB: 30 events

No significant difference among groups ALK 150 mg: 27% ALK 300 mg: 36% ALK 600 mg: 33% IRB: 37% Placebo: 32%

No significant difference among groups ALK 75 mg: 53% ALK 150 mg: 52% ALK 300 mg: 55% Placebo: 50%

No significant difference among groups ALK 37.5 mg: 22% ALK 75 mg: 35% ALK 150 mg: 25% ALK 300 mg: 23% LOS: 32%

Adverse Events

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Stanton R, DB, 21–70 197 et al38 active Years controlled

Design

DBP Reduction, mm Hg

2/4/08

Study

Blood No. Pressure, Patient of mm Age Patients Hg

Table I. Clinical studies of aliskiren (ALK) in hypertension management.

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J.W.M. Cheng

37

38 >18 Years

Duration

2779 DBP, ALK 75, 150, or 8 Weeks 95–109 300 mg daily alone and in combination with HCTZ 6.25, 12.5, or 25 mg daily or placebo

Regimen

ALK 75 mg: –8.7‡ ALK 150 mg: –8.9‡ ALK 300 mg: –10.3‡ HCTZ 6.25 mg: –9.1‡ HCTZ 12.5 mg: –10.1‡ HCTZ 25 mg: –9.4‡ ALK 75 mg + HCTZ 6.25 mg: –10.8‡ ALK 75 mg + HCTZ 12.5 mg: –11.1‡ ALK 75 mg + HCTZ 25 mg: –11.5‡ ALK 150 mg + HCTZ 6.25 mg: –10.4‡ ALK 150 mg + HCTZ 12.5 mg: –11.9‡ ALK 150 mg + HCTZ 25 mg: –12.7‡ ALK 300 mg + HCTZ 12.5 mg: –13.9‡ ALK 300 mg + HCTZ 25 mg: –14.3‡ Placebo: –6.9

ALK 75 mg: –9.4‡ ALK 150 mg: –12.2‡ ALK 300 mg: –15.7‡ HCTZ 6.25 mg: –11‡ HCTZ 12.5 mg: –13.9‡ HCTZ 25 mg: –14.3‡ ALK 75 mg + HCTZ 6.25: –14.3‡ ALK 75 mg + HCTZ 12.5 mg: –15.6‡ ALK 75 mg + HCTZ 25 mg: –17.3‡ ALK 150 mg + HCTZ 6.25 mg: –15.3‡ ALK 150 mg + HCTZ 12.5 mg: –17.6‡ ALK 150 mg + HCTZ 25 mg: –19.5‡ ALK 300 mg + HCTZ 12.5 mg: –19.8‡ ALK 300 mg + HCTZ 25 mg: –21.2‡ Placebo: –7.5

IRB: –11.0 vs IRB: –6.5 vs ALK 75 mg + IRB: –8.2 ALK 75 mg + IRB: –14.8 vs ALK vs ALK 150 mg + 150 mg + IRB: –13.3 IRB: –6.8

SBP Reduction, mm Hg

(continued)

No significant difference among groups ALK: 37.3%–39.2% HCTZ: 38.7%–42% ALK + HCTZ: 34.6%–45.3% Placebo: 44%

Adverse Events

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Villamil R, DB, et al42 placebo controlled

Design

DBP Reduction, mm Hg

2/4/08

Study

Blood No. Pressure, Patient of mm Age Patients Hg

Table I. (Continued)

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R, DB, placebo controlled

R, DB, placebo controlled

Pool et al43

Oh et al44

>18 Years

>18 Years

ALK 150 mg: –10.3‡ ALK 300 mg: –11.1‡ ALK 600 mg: –12.5‡ Placebo: –4.9

8 Weeks

672

DBP, ALK 150, 300, or 95–109 600 mg daily or placebo

ALK 75 mg: –10.3 ALK 150 mg: –10.3 ALK 300 mg: –12.3‡ VAL 80 mg: –10.5 VAL 160 mg: –11‡ VAL 320 mg: –11.3‡ ALK 75 mg + VAL 80 mg: –11.8‡ ALK 150 mg + VAL 160 mg: –12.1‡ ALK 300 mg + VAL 320 mg: –12.9‡ VAL 160 mg + HCTZ 12.5 mg: –13.5‡ Placebo: –8.6

Duration

1123 DBP, ALK 75, 150, or 8 Weeks 95–109 300 mg daily alone or in combination with VAL 80, 160, or 320 mg Or VAL 80, 160, or 320 mg Or a combination of VAL 160 mg and HCTZ 12.5 mg Or placebo

Regimen

DBP Reduction, mm Hg

ALK 150 mg: –13.0§ ALK 300 mg: –14.7§ ALK 600 mg: –15.8§ Placebo: –3.8

ALK 75 mg: –12.1 ALK 150 mg: –12.1 ALK 300 mg: –15.0§ VAL 80 mg: –11.2 VAL 160 mg: –15.5‡ VAL 320 mg: –16.5‡ ALK 75 mg + VAL 80 mg: –14.5‡ ALK 150 mg + VAL 160 mg: –16.6‡ ALK 300 mg + VAL 320 mg: –18‡ VAL 160 mg + HCTZ 12.5 mg: –18.9‡ Placebo: –10.0

SBP Reduction, mm Hg

(continued)

ALK 150 mg: 40.1% ALK 300 mg: 46.7% ALK 600 mg: 52.4% (significant increase in diarrhea with 600 mg, P < 0.001) Placebo: 43%

No significant difference among groups ALK 75 mg: 35.2% ALK 150 mg: 33.1% ALK 300 mg: 28.6% VAL 80 mg: 32.8% VAL 160 mg: 28.8% VAL 320 mg: 30% ALK 75 mg + VAL 80 mg: 33.3% ALK 150 mg + VAL 160 mg: 26.7% ALK 300 mg + VAL 320 mg: 31% VAL 160 mg + HCTZ 12.5 mg: 22% Placebo: 32.2%

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Design

Blood No. Pressure, Patient of mm Age Patients Hg

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Table I. (Continued)

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39

40 >18 Years

R, DB, placebo controlled

R, DB, placebo controlled

Jordan et al45

Oparil et al46

Duration

DBP, ALK 150 mg, IRB 12 Weeks 95–110 150 mg, AML 5 mg total daily, or placebo in addition to HCTZ 25 mg. After 4 weeks, the dose was doubled for ALK, IRB, and AML, then continued for 8 weeks

1797 DBP, ALK 150 mg for 95–110 4 weeks, then 300 mg for 4 weeks VAL 160 mg for 4 weeks, then 320 mg for 4 weeks ALK 150 mg + VAL 160 mg for 4 weeks, then ALK 300 mg + VAL 320 mg for 4 weeks Placebo for 8 weeks

489

Regimen

ALK: –9.0‡ VAL: –9.7‡ ALK 300 mg + VAL 320 mg: –12.2‡¶ Placebo: –4.1

ALK + HCTZ: –11.9¶ IRB + HCTZ: –11.3¶ AML + HCTZ: –10.3¶ Placebo + HCTZ: –7.9

DBP Reduction, mm Hg

ALK: –13.0# VAL: –12.8# ALK 300 mg + VAL 320 mg: –17.2# Placebo: –4.6

ALK + HCTZ: –15.8¶ IRB + HCTZ: –15.4¶ AML + HCTZ: –13.6¶ Placebo + HCTZ: –8.6

SBP Reduction, mm Hg

ALK: 34% VAL: 37% ALK + VAL: 35% Placebo: 37%

No significant difference among groups ALK + HCTZ: 39.3% IRB + HCTZ: 36.1% AML + HCTZ: 45.2% Placebo + HCTZ: 38.5%

Adverse Events

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DBP = diastolic blood pressure; SBP = systolic blood pressure; R = randomized; DB = double-blind; LOS = losartan; NA = not applicable; IRB = irbesartan; HCTZ = hydrochlorothiazide; RAM = ramipril; VAL = valsartan; AML = amlodipine. *P < 0.001 compared with baseline. † P < 0.05 compared with ALK 37.5 mg. ‡ P < 0.05 compared with placebo. § P < 0.001 compared with placebo. 㛳 P < 0.05 compared with IRB 150 mg. ¶ P < 0.05 compared with single agent. # P < 0.001 compared with single agent or placebo.

>18 Years

Design

Blood No. Pressure, Patient of mm Age Patients Hg

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Table I. (Continued)

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J.W.M. Cheng 150 mg was as effective as irbesartan 150 mg in lowering blood pressure. O’Brien et al41 conducted 3 open-label studies evaluating the antihypertensive effect and plasma renin activities in patients (age range, 18–80 years) with mean SBP ≥140 mm Hg but ≤180 mm Hg, receiving oral aliskiren 75 or 150 mg alone or in combination with HCTZ 25 mg (n = 23; 18 males, 5 females), ramipril 5 mg (n = 21; 17 males, 4 females), or irbesartan 150 mg (n = 23; 14 males, 9 females) for 3 weeks. No other antihypertensive agents were allowed during the study period. Patients were excluded if they could not withdraw from their antihypertensive medications, or if they had secondary or malignant hypertension, coronary artery disease, cerebrovascular disease, or any medical condition that might significantly alter the pharmacokinetic profile of aliskiren. In the HCTZ combination study, combination therapy (aliskiren 150 mg + HCTZ 25 mg) significantly reduced daytime but not nighttime SBP and DBP after 3 weeks of therapy, compared with aliskiren 150-mg monotherapy (SBP/DBP mean change: –18.4/–10.6 vs –10.4/ –5.8 mm Hg, P < 0.001 for both; nighttime: –15.6/ –8.1 vs –8.8/–5.0 mm Hg, P = 0.06). In the ramipril combination study, the combination treatment for 3 weeks further lowered both daytime and nighttime SBP/DBP compared with ramipril monotherapy (daytime: –10.5/–8.1 mm Hg [ramipril 5 mg + aliskiren 75 mg] and –14.0/–8.7 mm Hg [ramipril 5 mg + aliskiren 150 mg] vs –6.1/–5.9 mm Hg [ramipril 5 mg], P < 0.05 for both combinations compared with ramipril alone; nighttime: –8.1/–5.3 mm Hg [ramipril 5 mg + aliskiren 75 mg] and –9.6/–5.3 mm Hg [ramipril 5 mg + aliskiren 150 mg] vs –2.0/–0.7 mm Hg [ramipril 5 mg], P < 0.05 for both combinations compared with ramipril alone). In the irbesartan combination study, the combination treatment for 3 weeks resulted in significantly lower nighttime but not daytime SBP/DBP compared with irbesartan monotherapy (daytime: –14.8/–8.2 mm Hg [irbesartan 150 mg + aliskiren 75 mg] and –13.3/–6.8 mm Hg [irbesartan 150 mg + aliskiren 150 mg] vs –11.4/–6.5 mm Hg [irbesartan 150 mg alone], P = NS; nighttime: –16.1/–8.6 mm Hg [irbesartan 150 mg + aliskiren 75 mg] and –13.2/ –7.2 mm Hg [irbesartan 150 mg + aliskiren 150 mg] vs –9.0/–4.7 mm Hg [irbesartan alone], P < 0.05). This may be due to the use of suboptimal doses of irbesartan in this study. Aliskiren 150 mg alone significantly inhibited plasma renin activity by 65% (P < 0.001) January 2008

from baseline. In contrast, ramipril and irbesartan monotherapy were associated with 90% and 175% increases in plasma renin activity from baseline, respectively. However, when aliskiren was coadministered with HCTZ, ramipril, or irbesartan, plasma renin activity did not increase but remained similar to baseline levels. These results suggest that renin inhibition with aliskiren in these combinations increases RAAS suppression and, in some situations, improves blood pressure control. Aliskiren was well tolerated both as monotherapy and in combination. Specific adverse events were not reported in this study. Villamil et al42 performed an 8-week, randomized, double-blind, placebo-controlled trial comparing the antihypertensive effect of aliskiren (75, 150, or 300 mg), alone and in combination with HCTZ (6.25, 12.5, or 25 mg), in 2779 (1537 males, 1242 females; aged >18 years) patients with mean DBP of 95 to 109 mm Hg. No concurrent antihypertensive agents were allowed in the study. Patients were excluded if they were pregnant or breastfeeding, or had severe hypertension (SBP >180 mm Hg or DBP >110 mm Hg), history of secondary hypertension, DM, or any medical condition that might affect the pharmacokinetic profile of aliskiren. Aliskiren monotherapy was significantly better than placebo at reducing mean sitting SBP and DBP for all doses (P < 0.001 for all doses). Aliskiren 75, 150, or 300 mg reduced mean sitting SBP/DBP by –9.4/8.7, –12.2/–8.9, and –15.7/–10.3 mm Hg, respectively, and placebo reduced mean sitting SBP by –7.5/–6.9 mm Hg. Combination treatment was significantly better than both component monotherapy in reducing blood pressure (maximum mean sitting SBP/DBP reduction of –21.2/–14.3 mm Hg from baseline with aliskiren/HCTZ 300/25 mg vs –15.7/ –10.3 mm Hg for aliskiren 300 mg vs –14.3/–9.4 mm Hg for HCTZ 25 mg; P < 0.05 for aliskiren/HCTZ vs aliskiren alone and aliskiren/HCTZ vs HCTZ alone). Combination therapy also resulted in more responders (ie, patients with mean sitting DBP <90 mm Hg and/or a >10–mm Hg reduction) and better control rates (ie, patients achieving mean sitting SBP/DBP <140/90 mm Hg) than monotherapy (aliskiren 300 mg [63.9%], HCTZ 12.5 mg [60.6%], aliskiren 300 mg + HCTZ 12.5 mg [80.6%]; P < 0.05 for aliskiren/ HCTZ vs aliskiren alone and aliskiren/HCTZ vs HCTZ alone). Aliskiren monotherapy reduced plasma renin activity by up to 65% (P value not available) from baseline. Although HCTZ monotherapy in41

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Clinical Therapeutics creased plasma renin activity by up to 72% (P value not available), plasma renin activity decreased in all of the combination therapy groups. Aliskiren was well tolerated whether used alone or in combination with HCTZ. The incidence of adverse events was similar to placebo (37.3%–39.2% for aliskiren vs 44% for placebo). The most frequently reported adverse events included headache (7.2%) and nasopharyngitis (3.8%). It was concluded that aliskiren 300 mg, when used alone, significantly lowered blood pressure, and its effect was considerably greater when combined with HCTZ. Aliskiren was found to neutralize the compensatory rise in plasma renin activity induced by HCTZ. Pool et al43 examined the blood pressure–lowering effects of oral aliskiren, alone or in combination with valsartan, in 1123 patients (495 males, 628 females; aged >18 years) with mean DBP of 95 to 109 mm Hg. Patients were excluded if they had severe hypertension (SBP >180 mm Hg or DBP >110 mm Hg), DM, severe cardiac or cerebrovascular disease, life-threatening disease, or any medical condition that might affect the pharmacokinetic profile of aliskiren. No concurrent antihypertensive agents were allowed during the study period. Patients were randomized to receive QD, double-blind oral treatment with aliskiren monotherapy (75, 150, or 300 mg), valsartan monotherapy (80, 160, or 320 mg), aliskiren and valsartan in combination, valsartan/HCTZ (160/12.5 mg) in combination, or placebo for 8 weeks. Aliskiren 300 mg daily significantly (P < 0.001) lowered mean DBP and SBP compared with placebo (DBP, –12.3 vs –8.6 mm Hg, respectively; SBP, –15.0 vs –10.0 mm Hg, respectively). Unlike other studies,38–42,44–46 changes in blood pressure were not significantly different from placebo with other lower doses of aliskiren. Valsartan alone in doses of 160 or 320 mg daily, valsartan 160 mg in combination with HCTZ 12.5 mg, as well as any dose of valsartan combined with any dose of aliskiren, reduced DBP and SBP to a significantly greater extent than aliskiren 150 mg daily (P < 0.05 for all). In addition, valsartan 160 mg daily reduced SBP to a significantly greater extent than aliskiren 150 mg daily (P < 0.01), and valsartan 160 or 320 mg reduced DBP to a significantly greater extent than aliskiren 150 mg daily (P < 0.05). The investigators concluded that monotherapy with aliskiren 300 mg daily provided antihypertensive efficacy. When used in combination, aliskiren and valsartan provided additive blood pressure–lowering effects. Aliskiren was well tolerated when used alone or 42

in combination with HCTZ. The most commonly reported adverse events were headache (4.0%–8.4%, depending on dose), fatigue (2.2%–3.9%, depending on dose), and back pain (1.1%–2.2%, depending on dose). Oh et al44 evaluated the dose-related antihypertensive effect of aliskiren in 672 patients (414 males, 258 females; aged >18 years) with mean DBP of 95 to 109 mm Hg. Patients were excluded if they had severe hypertension (SBP >180 mm Hg or DBP >110 mm Hg) or a history of serious cardiac or cerebrovascular disease, DM, or any condition that might affect the pharmacokinetic profile of aliskiren. Patients were randomized to aliskiren 150, 300, or 600 mg or placebo QD for 8 weeks. No concurrent antihypertensive agents were allowed during the study. After completion of the treatment phase, patients entered a 2-week, treatment-free withdrawal period. Office blood pressure was recorded at baseline; weeks 2, 4, 6, and 8 of treatment; and 4 days and 2 weeks after cessation of treatment. A subgroup of 126 patients also underwent 24-hour ambulatory blood pressure monitoring. After 8 weeks, aliskiren 150, 300, and 600 mg significantly reduced mean blood pressure (SBP/DBP) by 13.0/ 10.3, 14.7/11.1, and 15.8/12.5 mm Hg, respectively, versus 3.8/4.9 mm Hg with placebo (P < 0.001 for SBP and DBP, for all groups compared with placebo). The blood pressure–lowering effect of aliskiren persisted for up to 2 weeks after treatment withdrawal. Aliskiren was also found to significantly reduce mean 24-hour ambulatory blood pressure (P < 0.001 vs placebo with all doses), exhibiting sustained effects throughout the day and high trough-to-peak ratios (0.64, 0.98, and 0.86 for 150, 300, and 600 mg, respectively). Aliskiren was well tolerated in this study, and the incidence of adverse events was similar to that of the placebo group. The most commonly reported adverse events included headache (5.4%–9.7%, depending on dose) and nasopharyngitis (1.8%–6.1%, depending on dose). This study suggested that aliskiren provides significant antihypertensive efficacy in patients, with no rebound effects on blood pressure after withdrawal. Jordan et al45 evaluated the antihypertensive effect of aliskiren in 489 obese patients (213 males, 276 females; body mass index, >30 kg/m2) aged >18 years who had mean DBP of 95 to 110 mm Hg at baseline and who were not responding to HCTZ 25 mg alone. Patients were excluded if they had secondary hyperVolume 30 Number 1

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J.W.M. Cheng tension, DM, history of severe cardiovascular or cerebrovascular disease, or other severe or life-threatening disease or medical condition that might significantly alter the pharmacokinetic profile of aliskiren. Patients were randomized to receive aliskiren 150 mg, irbesartan 150 mg, amlodipine 5 mg, or placebo for 4 weeks in addition to HCTZ 25 mg, followed by 8 weeks of doubling the initial dose of aliskiren, irbesartan, and amlodipine. No other concurrent antihypertensive agents were allowed during the study period. After 4 weeks of doubling dose treatment, aliskiren + HCTZ were found to significantly lower SBP/ DBP (15.8/ 11.9 mm Hg; P < 0.001) compared with HCTZ alone (8.6/7.9 mm Hg). The same combination provided a blood pressure reduction similar to those with irbesartan/ HCTZ and amlodipine/HCTZ (15.4/11.3 and 13.6/ 10.3 mm Hg, respectively). Tolerability of all doses and combinations was similar among groups. The most commonly reported adverse events included nasopharyngitis (4.1%–8.2% across treatment groups), headache (2.5%–7.1% across treatment groups), dizziness (0.8%–3.3% across treatment groups), and back pain (0.8%–4.1% across treatment groups). In this study, aliskiren was an effective and well-tolerated therapeutic alternative for obese patients with hypertension who could not achieve optimal blood pressure control with HCTZ alone. Oparil et al46 performed a double-blind, randomized, placebo-controlled study assessing the use of aliskiren 150 mg QD (n = 437), valsartan 160 mg daily (n = 455), a combination of aliskiren 150 mg and valsartan 160 mg daily (n = 446), and placebo (n = 459). After 4 weeks of therapy, the dosage in each group was doubled and continued for another 4 weeks. Patients enrolled were aged >18 years and had stage 1 or 2 hypertension (mean DBP, 95–110 mm Hg). Patients with history of severe cardiovascular or cerebrovascular disease or other severe life-threatening medical conditions were excluded. No other concurrent antihypertensive agents were allowed during the study period. The combination of aliskiren 300 mg and valsartan 320 mg was associated with a significantly lower mean SBP/DBP than aliskiren 300 mg daily, valsartan 320 mg daily, and placebo (–17.2/12.2 vs –13.0/9.0 mm Hg [P < 0.001], –12.8/9.7 mm Hg [P < 0.001], and –4.6/4.1 mm Hg [P < 0.001], respectively). Monotherapy with aliskiren and valsartan produced a similar blood pressure reduction effect. The incidence of adverse events was similar among treatJanuary 2008

ment groups (aliskiren, 34%; valsartan, 37%; aliskiren + valsartan, 35%; placebo, 37%). The most commonly reported adverse events were headache (3%–5% across treatment groups), nasopharyngitis (3%–4% across treatment groups), and dizziness (2% in all treatment groups). No patient discontinued therapy due to adverse events. Thus, the combination of aliskiren and valsartan at maximum recommended doses provided significantly greater blood pressure reduction without increasing the incidence of adverse events.

ADVERSE EVENTS, CONTRAINDICATIONS, AND PRECAUTIONS FOR ALISKIREN Aliskiren has been evaluated for tolerability in >6460 patients, including >1740 of them who used the drugs for >6 months’ duration and >1250 of them for >1 year.25 The total incidence of adverse events was similar to placebo and other comparative agents, including irbesartan, valsartan, losartan, ramipril, and HCTZ.38–46 The overall adverse-event rates were 22%, 35% to 52%, 25% to 52%, 34% to 55%, and 33% to 52% with aliskiren 37.5, 75, 150, 300, and 600 mg, respectively.38–46 The most commonly reported adverse events included headache, dizziness, and fatigue (incidence ranged from 2.4%–8.5% among studies).38–46 Aliskiren is also associated with doserelated gastrointestinal adverse events. Although the incidence of diarrhea reported with aliskiren up to 300 mg daily did not differ significantly from placebo, when aliskiren 600 mg daily was administered in one study, the incidence of diarrhea was significantly higher than that of placebo (11.4% vs 0.2%; P < 0.001).43 Because aliskiren directly affects the RAAS, adverse events experienced by patients using ACE inhibitors and ARBs, such as cough and angioedema, may also occur with aliskiren administration. To date, 2 cases of angioedema involving the respiratory system and 2 cases of periorbital edema have been reported in clinical studies with aliskiren, constituting a rate of 0.06%.25 In addition, 26 other cases of edema involving the face, hands, and whole body have been reported.25 Whether patients who experienced angioedema with ACE inhibitors will develop cross-sensitivity with aliskiren is unknown. Aliskiren use was associated with a slight increase in cough in placebo-controlled studies (1.1% for any aliskiren use vs 0.6% for placebo).38,39,43 In studies comparing aliskiren and ACE inhibitors, the rates of cough for aliskiren were about one third to one half the rates of ACE inhibitors.25 43

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Clinical Therapeutics Hyperkalemia was reported infrequently in aliskiren use (~0.9% vs ~0.6% in placebo). However, when used in combination with an ACE inhibitor, hyperkalemia occurred more frequently (~5.5%).25

Table II. Comparative cost of selected antihypertensive agents commonly used in the United States.47,48

DOSAGE AND ADMINISTRATION

Antihypertensive Agent

Aliskiren is available in 150- and 300-mg tablets. The usual recommended starting dose of aliskiren is 150 mg QD.25 Doses >300 mg did not provide an increased blood pressure response but did increase the rate of diarrhea by ~3-fold in one study.43 The antihypertensive effect of a given dose of aliskiren is attained after 2 weeks of therapy.25 No dosage adjustment is required when used in elderly patients (ie, those aged >65 years) or those with mild to severe renal impairment (creatinine clearance, <80 mL/min) or hepatic impairment (Child-Pugh Clinical Assessment score, 5–15).15,30,31

COST ASSESSMENT Because there are no outcome data available for costeffectiveness analysis, there have been no formal pharmacoeconomic assessments for aliskiren used in hypertension management published to date. The average wholesale price of aliskiren is $76.06 and $95.94 for a 30-day supply of 150- and 300-mg tablets, respectively.47,48 In terms of acquisition cost, aliskiren is more expensive than many alternative antihypertensive agents (Table II). Currently, no study has been performed evaluating the effect of aliskiren on longterm cardiovascular outcomes. Furthermore, it is not known whether patients who cannot tolerate ACE inhibitors or ARBs can be safely switched to aliskiren. Therefore, until such data become available, aliskiren should not be recommended as the drug of first choice in any patient for hypertension treatment, except for those who cannot tolerate other agents.

FUTURE PERSPECTIVES Medications that have direct effects on the RAAS— such as ACE inhibitors, ARBs, and aldosterone antagonists—have been found to not only effectively lower blood pressure but also to improve mortality and morbidity in patients with heart failure (ACE inhibitors, ARBs, and aldosterone antagonists), history of myocardial infarction (ACE inhibitors, ARBs, and aldosterone antagonists), and nephropathy (ACE inhibitors and ARBs).4–8 Aliskiren directly inhibits renin, and from a mechanism of action point of view, offers an advantage over ACE inhibitors and ARBs by in44

Aliskiren 150 mg daily 300 mg daily Captopril 12.5 mg TID 50 mg TID Enalapril 5 mg BID 20 mg BID Lisinopril 10 mg daily 40 mg daily Ramipril 5 mg daily 20 mg daily Losartan 25 mg daily 100 mg daily Valsartan 80 mg daily 320 mg daily Irbesartan 75 mg daily 300 mg daily Candesartan 4 mg daily 32 mg daily Hydrochlorothiazide 12.5 mg daily 25 mg daily Metoprolol 25 mg BID 100 mg BID Atenolol 25 mg daily 100 mg daily Carvedilol 3.125 mg BID 25 mg BID Diltiazem sustained release 180 mg daily 360 mg daily Amlodipine 5 mg daily 10 mg daily

Cost for 30-Day Supply (US $ [2008]) 76.06 95.94 12.99 10.00 11.33 13.98 12.99 19.99 59.99 130.64 58.99 79.99 65.99 101.99 55.99 69.99 55.95 74.00 12.00 4.00 10.65 13.99 4.00 5.30 29.98 29.97 51.44 91.25 37.99 51.99

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J.W.M. Cheng hibiting the rate-limiting step of angiotensin II formation and producing more effective and complete inhibition of angiotensin II. Whether such effects result in better protection from heart attack, stroke, myocardial infarction, and nephropathy is unknown. Whether the additive benefit in hypertension with the combination of aliskiren and ACE inhibitors or ARBs will extend to other indications is also unknown. The current literature review did not identify any published study performed evaluating the effect of aliskiren in long-term cardiovascular outcomes. Furthermore, it is not known whether patients who cannot tolerate ACE inhibitors or ARBs can be safely switched to aliskiren. Further research investigating these potential roles will help establish a place for aliskiren in cardiovascular disease management. There are ongoing studies evaluating the use of aliskiren in patients with postmyocardial infarction as well as in those with diabetic nephropathy.49

CONCLUSIONS Aliskiren is the first of a new class of antihypertensive agents known as renin inhibitors. Aliskiren can be administered in QD dosing. Results of pharmacokinetic and pharmacodynamic studies suggest that aliskiren has better inhibition of the RAAS compared with ACE inhibitors and ARBs. Because aliskiren is not renally eliminated and is not a significant substrate, inhibitor, or inducer of the CYP isozymes, the drug-interaction profile is not anticipated to be extensive. Aliskiren is well tolerated, with the most common adverse events reported as headache, dizziness, and fatigue. Clinical studies support the use of aliskiren in patients with mild to moderate hypertension (DBP, 95–109 mm Hg), alone or in combination with ACE inhibitors, ARBs, amlodipine, or diuretics. Future studies will provide more insights into the long-term effects of the use of renin inhibitors in hypertension treatment, as well as whether such treatment may alter cardiovascular outcomes.

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2. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [US Dept of Health and Human Services Web site]. http://www.nhlbi.nih.gov/guidelines/ hypertension/jnc7full.pdf. Accessed April 10, 2007. 3. Top 300 Prescriptions for 2005 [RxList.com Web site]. http://www.rxlist.com/script/main/art.asp?articlekey= 79509. Accessed April 10, 2007. 4. Linn WD. Angiotensin-converting enzyme inhibitors in left ventricular dysfunction. Pharmacotherapy. 1996;16:50S–58S. 5. Maggioni AP. Efficacy of angiotensin receptor blockers in cardiovascular disease. Cardiovasc Drugs Ther. 2006;20:295– 308. 6. Hilleman DE, Lucas BD Jr. Angiotensin-converting enzyme inhibitors and stroke risk: Benefit beyond blood pressure reduction? Pharmacotherapy. 2004;24:1064–1076. 7. Strippoli GF, Craig M, Deeks JJ, et al. Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: Systematic review. BMJ. 2004;329:828. 8. Greenberg B, Zannad F, Pitt B. Role of aldosterone blockade for treatment of heart failure and post-acute myocardial infarction. Am J Cardiol. 2006;97:34F–40F. 9. FDA approves new drug treatment for high blood pressure [FDA Web site]. http://www.fda.gov/bbs/topics/NEWS/ 2007/NEW01580.html. Accessed April 15, 2007. 10. Jandeleit-Dahm K, Cooper ME. Hypertension and diabetes: Role of the renin–angiotensin system. Endocrinol Metab Clin North Am. 2006;35:469–490, vii. 11. Dzau VJ. Theodore Cooper Lecture: Tissue angiotensin and pathobiology of vascular disease: A unifying hypothesis. Hypertension. 2001;37:1047–1052. 12. Kostis JB. Angiotensin converting enzyme inhibitors. I. Pharmacology. Am Heart J. 1988;116:1580–1591. 13. Mimran A, Ribstein J. Angiotensin receptor blockers: Pharmacology and clinical significance. J Am Soc Nephrol. 1999; 10(Suppl 12):S273–S277. 14. Brown NJ. Eplerenone: Cardiovascular protection. Circulation. 2003;107:2512–2518. 15. Urata H, Kinoshita A, Misono KS, et al. Identification of a highly specific chymase as the major angiotensin II– forming enzyme in the human heart [published correction appears in J Biol Chem. 1991;266:12114]. J Biol Chem. 1990;265:22348–22357. 16. Okunishi H, Miyazaki M, Toda N. Evidence for a putatively new angiotensin II–generating enzyme in the vascular wall. J Hypertens. 1984;2:277–284. 17. Hollenberg NK, Fisher ND, Price DA. Pathways for angiotensin II generation in intact human tissue: Evidence from comparative pharmacological interruption of the renin system. Hypertension. 1998;32:387–392. 18. Saris JJ, van Dijk MA, Kroon I, et al. Functional importance of angiotensin-converting enzyme-dependent in situ angio-

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vides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol. 2007;49: 1157–1163. Jordan J, Engeli S, Boye SW, et al. Direct renin inhibition with aliskiren in obese patients with arterial hypertension. Hypertension. 2007;49:1047– 1055. Oparil S, Yarows SA, Patel S, et al. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: A randomised, double-blind trial [published correction appears in Lancet. 2007;370: 1542]. Lancet. 2007;370:221–229. Aliskiren (Tekturna) [product information] [California Pharmacists Association Web site]. http://cpha-com. web09.winsvr.net/pdf/iRx-CaliforniaTekturna.pdf. Accessed January 4, 2008. Prescription price checker [drugstore.com Web site]. http://www. drugstore.com/pharmacy/drugindex/ default.asp?trx=1Z5015. Accessed January 4, 2008. Aliskiren Clinical Trials. http://www. clinicaltrials.gov/ct/action/GetStudy. Accessed September 26, 2007.

Address correspondence to: Judy W.M. Cheng, BS, PharmD, MPH, FCCP, BCPS, Massachusetts College of Pharmacy and Health Sciences, Division of Pharmacy Practice, 179 Longwood Avenue, Boston, MA 02115. E-mail: [email protected] January 2008

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