Safety and Tolerability of the Direct Renin Inhibitor Aliskiren in Combination With Angiotensin Receptor Blockers and Thiazide Diuretics: A Pooled Analysis of Clinical Experience of 12,942 Patients

Authors


William B. White, MD, Division of Hypertension and Clinical Pharmacology, Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, CT 06030-3940
E-mail: wwhite@nso1.uchc.edu

Abstract

J Clin Hypertens (Greenwich). 2011;13:506–516. ©2011 Wiley Periodicals, Inc.

Combinations of the direct renin inhibitor aliskiren with angiotensin receptor blockers (ARBs) or diuretics are effective therapeutic regimens for the treatment of hypertension. A large database of safety information has become available during the past several years with aliskiren in combination trials. Data were pooled from 9 short-term (8-week) and 4 longer-term (26- to 52-week) randomized controlled trials of aliskiren in patients with hypertension. Adverse event (AE) rates were assessed for aliskiren combination therapy compared with component monotherapies. In short-term studies, overall AE rates were similar for patients receiving aliskiren/valsartan or aliskiren/diuretic combinations (32.2%–39.8%) and those receiving the component monotherapies (30.0%–39.6%). In longer-term studies, AE rates with aliskiren/losartan (55.5%) and aliskiren/diuretic (45.0%) combination therapy were similar to those with losartan (53.9%) and diuretic (48.9%) alone. Angioedema and hyperkalemia occurred in similar proportions of patients taking combination therapies vs monotherapy. The safety and tolerability profile of aliskiren in combination with the ARBs valsartan or losartan, or diuretic, is similar to aliskiren, ARBs, or diuretics alone.

Many patients with hypertension require ≥2 antihypertensive agents to achieve recommended blood pressure (BP) goals (<140/90 mm Hg). Accordingly, current US and European treatment guidelines advocate that combination treatment should be considered as a first-line option for patients who have high initial BP (eg, systolic BP >20 mm Hg above goal [<140 mm Hg] or diastolic BP >10 mm Hg above goal [<90 mm Hg]).1,2 European guidelines also recommend combination therapy for patients with lesser degrees of BP elevation when other cardiovascular (CV) risk factors, such as target organ damage, renal disease, or a history of CV disease, are present.2 These recommendations reflect recent clinical trial evidence that the larger and more rapid reductions in BP conferred by early use of combination therapy and consequent prompt achievement of BP goals is associated with increased protection from CV events.3

It is clinically relevant to evaluate the safety profiles of fixed combinations of antihypertensive medications that promote effective BP reduction. The combination of drugs that target the renin-angiotensin system (RAS) with thiazide diuretics is a widely used therapeutic approach. In 2007, the first oral direct renin inhibitor, aliskiren, became available for the treatment of hypertension. Since aliskiren has a different mechanism of action compared with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), it is possible that it may have a different safety profile to these agents. Clinical trials have shown that aliskiren is effective for reducing BP in patients with hypertension, when given alone or in combination with other antihypertensive therapies.4–13

In 2006, an independently chaired, multidisciplinary aliskiren global safety committee was formed and funded by Novartis to analyze and review semi-annually all safety data related to aliskiren clinical trials of patients with hypertension and related comorbid populations. The committee evaluated safety data pooled from short-term, placebo-controlled and longer-term, active-controlled aliskiren clinical trials, and has previously reported its findings for aliskiren monotherapy.14 In the present study, we report on clinical trial safety data for aliskiren in combination with ARBs and thiazide diuretics.

Methods

Description of the Pooled Trials

Safety data from aliskiren studies were pooled every 6 months on an ongoing basis. All studies with a database lock before August 31, 2009, were included. Thirty-two studies were included in the pooled data set. Of these, 13 studies were excluded from the present analysis because they were not placebo-controlled, 4 studies were excluded because they had an open-label study design, and 2 studies were excluded because they were not studies of hypertension. Therefore, safety data from 13 randomized, double-blind clinical trials in patients with hypertension were evaluated: 9 short-term (8-week) placebo-controlled studies9,12,15–21 and 4 longer-term (26- to 52-week) active-controlled studies.6,10,22,23 The current analysis assessed the safety of aliskiren in combination with ARBs or thiazide diuretics. Most studies enrolled patients with stage 1 or 2 hypertension (seated diastolic BP ≥90 mm Hg or ≥95 mm Hg and <110 mm Hg); 3 trials enrolled special populations (1 included only overweight patients with left ventricular hypertrophy, and 2 included only patients aged 65 years and older with systolic hypertension [seated systolic BP of 140 mm Hg or 150 mm Hg to <180 mm Hg and diastolic BP <110 mm Hg]). Exclusion criteria were generally similar across the studies and included secondary hypertension, history of severe CV disease, type 1 or uncontrolled type 2 diabetes, and clinically significant hepatic, renal, or endocrine disorders.

Adverse Events: Search Terms

All adverse events (AEs) that occurred during the treatment period of the studies were tabulated. The most common AEs are presented. In addition, the pooled databases were searched for events of special interest that are related to agents that target the RAS, such as aliskiren: angioedema/urticaria, cough, rash, hypotension, hyperkalemia, peripheral edema, renal dysfunction, diarrhea, and colorectal events.24–31 The searches for events of special interest used broad terms that captured a wide variety of events. For example, the search for angioedema/urticaria included urticaria, edema of the head, neck, and mucous membranes; the search for hypotension included dizziness, syncope, vertigo, and positional vertigo; and the search for colorectal events included gastrointestinal neoplasms (benign and malignant), gastrointestinal hemorrhages, ulceration, and perforation.

This analysis also assessed all serious AEs, regardless of whether they were classed as being of special interest. Serious AEs were defined by guidelines from the International Conference on Harmonization-Good Clinical Practice (ICH-GCP). In brief, a serious AE is defined as one that is fatal or life-threatening, results in persistent or significant disability or incapacity, constitutes a congenital anomaly or birth defect, requires inpatient hospitalization or prolongation of existing hospitalization, or is otherwise medically significant.

Statistical Methods

Demographics, baseline characteristics, AEs of special interest, and laboratory abnormalities were summarized by pooled treatment group, according to the treatment to which patients were randomized, regardless of doses used during any titration period. Pooled treatment groups for the short-term, placebo-controlled and longer-term, active-controlled studies included aliskiren 150 mg, aliskiren 300 mg, aliskiren monotherapy (150 mg or 300 mg), aliskiren/ARB combination therapy, aliskiren/thiazide diuretic combination therapy, ARB monotherapy, and thiazide diuretic monotherapy.

Pair-wise comparisons were performed for the AEs of special interest (excluding regimens using the unlicensed 75-mg and 600-mg doses of aliskiren). Relative risks (RRs) with associated 95% confidence intervals (CIs) were determined for aliskiren/ARB combination therapy vs ARB monotherapy (aliskiren/valsartan vs pooled valsartan, irbesartan and losartan for short-term studies; aliskiren/losartan for losartan for longer-term studies); aliskiren/ARB combination therapy vs aliskiren monotherapy (short- and longer-term studies); aliskiren/thiazide diuretic combination therapy vs thiazide diuretic monotherapy (short-term studies); and aliskiren and thiazide diuretic combination therapy vs aliskiren monotherapy (short-term studies). For the longer-term trials, RRs were calculated for individual studies rather than for treatment groups pooled across studies, due to differences in study design and thus length of exposure.

Results

Patients and Exposure

Safety data were available for 12,942 patients: 9616 patients from the short-term, placebo-controlled studies and 3326 patients from the longer-term, active-controlled studies. The cumulative exposure to study medication ranged from 82.6 patient-years to 245.6 patient-years in short-term placebo-controlled studies, and from 99.6 patient-years to 548.0 patient-years in longer-term, active controlled studies.

Baseline Patient Characteristics

Baseline characteristics of patients were generally similar between the monotherapy and combination therapy treatment groups (Table I). In the short-term studies, the aliskiren/valsartan group contained a greater proportion of obese patients (44.7%) than the aliskiren or ARB (pooled valsartan, irbesartan and losartan) monotherapy groups (29.2%–38.8%). Similarly, the aliskiren/losartan combination therapy and losartan monotherapy groups in the longer-term studies contained a greater proportion of patients who were obese (56.1% and 50.0%) than did the aliskiren monotherapy groups (40.7%–41.9%), and a greater proportion of patients who had diabetes (27.1% and 22.1% vs 13.4%–16.1%). In the short- and longer-term studies, baseline characteristics were similar between the aliskiren/hydrochlorothiazide (HCT) combination therapy and aliskiren and HCT monotherapy groups.

Table I.   Baseline Patient Characteristics
(A) Short-Term, Placebo-Controlled Studies
Baseline CharacteristicAliskiren (150 mg)
n=1435
Aliskiren (300 mg)
n=1551
Aliskiren/HCTan=1464HCTb
n=555
Aliskiren/Valsartanc
n=624
ARBd
n=1069
Age, mean±SD, y  55.8±12.4  55.8±12.1  54.6±11.255.2±12.2   53.4±10.953.4±10.9
Age group, No. (%)
 <65 y1034 (72.1)1146 (73.9)1177 (80.4)415 (74.8)525 (84.1)901 (84.3)
 ≥65 y401 (27.9)405 (26.1)287 (19.6)140 (25.2)99 (15.9)168 (15.7)
 ≥75 y94 (6.6)97 (6.3)44 (3.0)21 (3.8)14 (2.2)26 (2.4)
Male, No. (%)881 (61.4)870 (56.1)792 (54.1)302 (54.4)372 (59.6)666 (62.3)
Race, No. (%)
 Caucasian847 (59.0)1172 (75.6)1261 (86.1)474 (85.4)500 (80.1)587 (54.9)
 Black88 (6.1)142 (9.2)62 (4.2)31 (5.6)74 (11.9)129 (12.1)
 Asian452 (31.5)157 (10.1)39 (2.7)12 (2.2)8 (1.3)311 (29.1)
 Other48 (3.3)80 (5.2)102 (7.0)38 (6.8)42 (6.7)42 (3.9)
BMI, mean±SD, kg/m228.2±5.229.5±5.629.4±5.429.4±5.530.2±5.629.2±5.6
Obese (BMI ≥30 kg/m2), No. (%)419 (29.2)602 (38.8)557 (38.0)204 (36.8)279 (44.7)390 (36.5)
Diabetes, No. (%)133 (9.3)165 (10.6)112 (7.7)42 (7.6)64 (10.3)95 (8.9)
Duration of hypertension, mean±SD, y7.1±7.18.3±7.67.6±7.37.8±8.08.0±7.77.4±7.4
Sitting SBP, mean±SD, mm Hg153.9±11.8154.2±11.6153.7±12.3153.8±12.1153.0±12.4153.5±11.8
Sitting DBP, mean±SD, mm Hg98.0±5.698.6±5.699.2±3.699.2±3.499.7±4.099.7±4.0
Baseline renal function (eGFR), No. (%)
 <60 mL/min/1.73 m261 (4.3)69 (4.4)61 (4.2)20 (3.6)18 (2.9)30 (2.8)
 ≥60 to <90 mL/ min/1.73 m2685 (47.7)806 (52.0)807 (55.1)304 (54.8)324 (51.9)469 (43.9)
 ≥90 mL/min/1.73 m2689 (48.0)663 (42.7)596 (40.7)231 (41.6)270 (43.3)565 (52.9)
 No data available013 (0.8)0012 (1.9)5 (0.5)
(B) Longer-Term, Active-Controlled Studies
Baseline CharacteristicAliskiren Monotherapy (150 or 300 mg)
n=1593
Aliskiren (150 mg)
n=871
Aliskiren (300 mg)
n=722
HCTe
n=558
Aliskiren/Losartanf
n=155
Losartang
n=154
  1. Abbreviations: ARB, angiotensin receptor blocker; BMI, body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HCT, hydrochlorothiazide; SBP, systolic blood pressure; SD, standard deviation. Data are summarized according to the treatment to which patients were randomized. aAliskiren/HCT 150/6.25 mg to 300/25 mg. b6.25 to 25 mg. cAliskiren/valsartan 75/80 mg to 300/320 mg. dLosartan 50 mg, irbesartan 150 mg, or valsartan 80 mg to 320 mg. eHCT 12.5 mg to 25 mg; HCT/amlodipine 25/5 mg to 10 mg (in one study, amlodipine was added to HCT if blood pressure was not controlled to <140/90 mm Hg).22 fAliskiren/losartan 150/50 mg to 300/100 mg. gLosartan 50 mg to 100 mg.

Age, mean±SD, y   60.1±12.2  63.1±12.6   56.6±10.755.8±10.9   58.8±10.659.1±11.0
Age group, No. (%)
 <65 y903 (56.7)356 (40.9)547 (75.8)430 (77.1)108 (69.7)101 (65.6)
 ≥65 y690 (43.3)515 (59.1)175 (24.2)128 (22.9)47 (30.3)53 (34.4)
 ≥75 y179 (11.2)156 (17.9)23 (3.2)19 (3.4)5 (3.2)8 (5.2)
Male, No. (%)863 (54.2)443 (50.9)420 (58.2)312 (55.9)120 (77.4)118 (76.6)
Race, No. (%)
 Caucasian1402 (88.0)696 (79.9)706 (97.8)553 (99.1)147 (94.8)145 (94.2)
 Black118 (7.4)117 (13.4)1 (0.1)01 (0.6)2 (1.3)
 Asian37 (2.3)32 (3.7)5 (0.7)4 (0.7)1 (0.6)0
 Other36 (2.3)26 (3.0)10 (1.4)1 (0.2)6 (3.9)7 (4.5)
BMI, mean±SD, kg/m229.7±5.329.9±5.829.4±4.629.1±4.831.3±4.030.8±4.1
Obese (BMI ≥30 kg/m2), No. (%)659 (41.4)365 (41.9)294 (40.7)188 (33.7)87 (56.1)77 (50.0)
Diabetes, No. (%)237 (14.9)140 (16.1)97 (13.4)60 (10.8)42 (27.1)34 (22.1)
Duration of hypertension, mean±SD, y9.0±8.79.8±9.48.1±7.66.9±6.812.7±10.112.3±9.1
Sitting SBP, mean±SD, mm Hg153.3±12.0154.1±11.6152.4±12.4154.3±11.0144.4±13.9146.3±13.4
Sitting DBP, mean±SD, mm Hg94.2±8.891.9±9.896.8±6.799.0±3.488.4±8.589.1±10.1
Baseline renal function (eGFR), No. (%)
 <60 mL/min/1.73 m2146 (9.2)113 (13.0)33 (4.6)38 (6.8)12 (7.7)13 (8.4)
 ≥60 to <90 mL/min/1.73 m2896 (56.2)474 (54.4)422 (58.4)336 (60.2)88 (56.8)91 (59.1)
 ≥90 mL/min/1.73 m2549 (34.5)282 (32.4)267 (37.0)184 (33.0)55 (35.5)50 (32.5)
 No data available2 (0.1)2 (0.2)0000

Serious AEs

Overall, 0.7% of patients in the short-term studies and 4.5% of patients in the longer-term studies had a serious AE. In the short-term studies, serious AEs were experienced by a similar proportion of patients who received aliskiren in combination with valsartan (0.6%) to those who received aliskiren monotherapy (150 mg, 0.5%; 300 mg, 0.4%), ARB (valsartan 80 mg–320 mg, irbesartan 150 mg, or losartan 50 mg) monotherapy (0.8%), or placebo (0.7%). The incidence of serious AEs with aliskiren/thiazide diuretic combination therapy (1.1%) was similar to that with thiazide diuretic monotherapy (0.9%) and slightly greater than that with aliskiren monotherapy (150 mg, 0.5%; 300 mg, 0.4%) or placebo (0.7%). In the longer-term studies, the proportion of patients who experienced serious AEs while receiving combination therapy with aliskiren/losartan (5.2%) was lower than that in patients receiving losartan monotherapy (8.4%) and similar to that in patients receiving aliskiren monotherapy (3.4%). For the aliskiren/thiazide diuretic combination, the proportion of patients who experienced serious AEs (2.5%) was similar to that for each of the individual monotherapies (3.4% and 1.7% for aliskiren and thiazide diuretic monotherapy, respectively). Most of the serious AEs in each treatment group were experienced by only 1 patient, and there was no apparent clustering of events.

Any AE

In the short-term studies, AEs were experienced by a similar proportion of patients receiving combination therapy with aliskiren/valsartan or with aliskiren/thiazide diuretic (32.2%–39.8%) to those receiving the individual agents as monotherapy (30.0%–39.6%) or placebo (35%). In the longer-term studies, the proportion of patients who experienced AEs with aliskiren/losartan and aliskiren/thiazide diuretic combination therapy (55.5% and 45.0%, respectively) was similar to those receiving losartan monotherapy and thiazide diuretic monotherapy (53.9% and 48.9%, respectively). Discontinuations due to AEs were uncommon (≤1.9% in the short-term studies and ≤5.9% in the longer-term studies). A smaller proportion of patients discontinued with combination treatment than with the component monotherapies in the longer-term studies (aliskiren/losartan, 1.9%; aliskiren/thiazide diuretic, 1.8%; losartan monotherapy, 6.5%; thiazide diuretic monotherapy, 3.3%; and aliskiren monotherapy, 4.3%).

In the short-term studies, the most common AEs were headache, nasopharyngitis, and diarrhea (Table IIA). The incidences of individual AEs were generally similar between treatments, although there was a higher rate of headache in the aliskiren/HCT combination therapy and HCT monotherapy groups (6.5% and 7.0%, respectively) than in the other treatment groups (3.6%–4.5%). The most common AEs in the long-term studies were headache, dizziness, nasopharyngitis, and diarrhea (Table IIB). The rates of individual AEs were generally low. The incidence of nasopharyngitis was higher with aliskiren/losartan combination therapy (7.1%) and losartan monotherapy (8.4%) than with the other treatments (1.7%–3.0%).

Table II.   Any Adverse Event
(A) Short-Term, Placebo-Controlled Studies
Adverse EventAliskiren Monotherapy (150 mg or 300 mg)
n=3380
Aliskiren (150 mg)
n=1872
Aliskiren
(300 mg)
n=1508
Aliskiren/HCTa
n=1464
HCTb
n=555
Aliskiren/Valsartanc
n=624
ARBd
n=1069
Most frequent adverse events occurring in ≥1% of patients in any group
 Headache126 (3.7)67 (3.6)59 (3.9)   95 (6.5)39 (7.0) 28 (4.5)48 (4.5)
 Nasopharyngitis135 (4.0)92 (4.9)43 (2.9)56 (3.8)21 (3.8)15 (2.4)63 (5.9)
 Diarrhea40 (1.2)17 (0.9)23 (1.5)24 (1.6)10 (1.8)9 (1.4)11 (1.0)
 Dizziness46 (1.4)20 (1.1)26 (1.7)34 (2.3)13 (2.3)10 (1.6)21 (2.0)
 Back pain34 (1.0)19 (1.0)15 (1.0)21 (1.4)6 (1.1)10 (1.6)20 (1.9)
 Fatigue28 (0.8)10 (0.5)18 (1.2)13 (0.9)6 (1.1)16 (2.6)16 (1.5)
 Upper respiratory tract infection30 (0.9)13 (0.7)17 (1.1)16 (1.1)4 (0.7)8 (1.3)10 (0.9)
 Bronchitis31 (0.9)14 (0.7)17 (1.1)17 (1.2)4 (0.7)6 (1.0)12 (1.1)
 Nausea27 (0.8)10 (0.5)17 (1.1)17 (1.2)6 (1.1)9 (1.4)12 (1.1)
 Cough31 (0.9)20 (1.1)11 (0.7)19 (1.3)4 (0.7)3 (0.5)3 (0.3)
 Edema peripheral21 (0.6)11 (0.6)10 (0.7)13 (0.9)6 (1.1)1 (0.2)5 (0.5)
(B) Longer-Term, Active-Controlled Studies
Adverse EventAliskiren Monotherapy (150 mg and 300 mg)
n=2784
Aliskiren (150 mg)
n=1487
Aliskiren (300 mg)
n=1297
HCTe
n=544
Aliskiren/ Losartanf
n=155
Losartang
n=154
  1. Abbreviations: ARB, angiotensin receptor blocker; HCT, hydrochlorothiazide. Values are expressed as number (percentage) of patients and are summarized according to treatment to received. aAliskiren/HCT 150/6.25 mg to 300/25 mg. b6.25 mg to 25 mg. cAliskiren/valsartan 150/160 mg to 300/320 mg. dLosartan 50 mg, irbesartan 150 mg, or valsartan 80 mg to 320 mg. eHCT 12.5 to 25 mg; HCT/amlodipine 25/5 mg to 10 mg (in one study, amlodipine was added to HCT if blood pressure was not controlled to <140/90 mm Hg).22 fAliskiren/losartan 150/50 mg to 300/100 mg. gLosartan 50 to 100 mg.

Most frequent adverse events occurring in ≥2% of patients in any group
 Headache128 (4.6)77 (5.2)    51 (3.9)33 (6.1) 10 (6.5)8 (5.2)
 Dizziness63 (2.3)37 (2.5)26 (2.0)19 (3.5)8 (5.2)3 (1.9)
 Nasopharyngitis64 (2.3)25 (1.7)39 (3.0)16 (2.9)11 (7.1)13 (8.4)
 Diarrhea62 (2.2)28 (1.9)34 (2.6)8 (1.5)7 (4.5)9 (5.8)
 Cough49 (1.8)21 (1.4)28 (2.2)14 (2.6)2 (1.3)3 (1.9)
 Back pain47 (1.7)23 (1.5)24 (1.9)16 (2.9)2 (1.3)4 (2.6)
 Upper respiratory tract infection48 (1.7)26 (1.7)22 (1.7)2 (0.4)1 (0.6)1 (0.6)
 Bronchitis38 (1.4)7 (0.5)31 (2.4)15 (2.8)3 (1.9)3 (1.9)
 Arthralgia36 (1.3)15 (1.0)21 (1.6)13 (2.4)1 (0.6)3 (1.9)
 Dyspepsia25 (0.9)11 (0.7)14 (1.1)4 (0.7)5 (3.2)3 (1.9)
 Influenza21 (0.8)3 (0.2)18 (1.4)8 (1.5)6 (3.9)7 (4.5)
 Hypercholesterolemia18 (0.6)15 (1.0)3 (0.2)14 (2.6)1 (0.6)0
 Asthenia17 (0.6)11 (0.7)6 (0.5)5 (0.9)2 (1.3)4 (2.6)

Laboratory Abnormalities

Fewer than 1% of patients in any treatment group had prespecified laboratory abnormalities of blood urea nitrogen >40 mg/dL, creatinine >2.0 mg/dL, or estimated glomerular filtration rate <30 mL/min/1.73 m2. As expected, elevated serum potassium (>5.5 mEq/L) was found in a greater proportion of patients receiving short-term treatment with aliskiren/valsartan than in those receiving the individual monotherapies (3.4% vs 1.3% for aliskiren and 0.7% for ARBs) (Table IIIA). Elevations in serum potassium levels to ≥6.0 mEq/L were observed in similar proportions of patients in these treatment groups (0.3% with aliskiren/valsartan compared with 0.4% with aliskiren monotherapy and 0.5% with ARB [valsartan, irbesartan or losartan] monotherapy). There were no differences between treatments in the rates of serum potassium >5.5 mEq/L in the longer-term studies: 3.3% of patients receiving aliskiren/losartan compared with 3.6% receiving aliskiren monotherapy and 3.3% receiving losartan monotherapy (Table IIIB).

Table III.   Prespecified Laboratory Abnormalities
(A) Short-Term, Placebo-Controlled Studies
Laboratory VariableAliskiren (150 mg)
n=1435
Aliskiren
(300 mg)
n=1551
Aliskiren/HCTa
n=1464
HCTb
n=555
Aliskiren/ Valsartanc
n=624
ARBd (50–300 mg)
n=1069
Potassium level
 <3.5 mEq/L 13 (1.0)  19 (1.3)  21 (1.8)14 (3.1)  13 (2.2)  26 (2.5)
 >5.5 mEq/L14 (1.0)24 (1.7)6 (0.5)4 (0.9)20 (3.4)7 (0.7)
 ≥6.0 mEq/L5 (0.4)7 (0.5)1 (0.1)1 (0.2)2 (0.3)5 (0.5)
 ≥7.0 mEq/L03 (0.2)002 (0.3)2 (0.2)
BUN >40 mg/dL03 (0.2)0001 (0.1)
Creatinine level >2.0 mg/dL04 (0.3)004 (0.7)2 (0.2)
eGFR <30 mL/min/1.73 m201 (0.1)002 (0.3)1 (0.1)
(B) Longer-Term, Active-Controlled Studies
Laboratory VariableAliskiren Monotherapy (150 and 300 mg)
n=1593
Aliskiren (150 mg)
n=871
Aliskiren 
(300 mg)
n=722
HCTe
n=558
Aliskiren/ losartanf
n=155
Losartang
n=154
  1. Abbreviations: ARB, angiotensin receptor blocker; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; HCT, hydrochlorothiazide. Values are expressed as number (percentage) of patients who had laboratory measurements and are summarized according to the treatment to which patients were randomized. aAliskiren/HCT 150/6.25 mg to 300/25 mg. b6.25 to 25 mg. cAliskiren/valsartan 75/80 mg to 300/320 mg. dLosartan 50 mg, irbesartan 150 mg, or valsartan 80 mg to 320 mg. eHCT 12.5 mg to 25 mg; HCT/amlodipine 25/5 mg to 10 mg (in one study, amlodipine was added to HCT if blood pressure was not controlled to <140/90 mm Hg).22 fAliskiren/losartan 150/50 mg to 300/100 mg. gLosartan 50 mg to 100 mg.

Potassium level
 <3.5 mEq/L   54 (3.5)37 (4.4)17 (2.4)96 (17.8)  8 (5.2)11 (7.2)
 >5.5 mEq/L56 (3.6)16 (1.9)40 (5.7)20 (3.7)5 (3.3)5 (3.3)
 ≥6.0 mEq/L25 (1.6)7 (0.8)18 (2.6)10 (1.9)1 (0.7)1 (0.7)
 ≥7.0 mEq/L5 (0.3)05 (0.7)3 (0.6)01 (0.7)
BUN >40 mg/dL10 (0.6)6 (0.7)4 (0.6)4 (0.7)02 (1.3)
Creatinine level >2.0 mg/dL4 (0.3)2 (0.2)2 (0.3)01 (0.7)1 (0.7)
eGFR <30 mL/min/1.73 m25 (0.3)3 (0.4)2 (0.3)01 (0.7)2 (1.3)

All AEs of Special Interest

There were no statistically significant increases in the RR of any of the AEs of special interest with aliskiren/ARB (aliskiren/valsartan for short-term studies, or aliskiren/losartan for longer-term studies) compared with aliskiren monotherapy or ARB (valsartan, irbesartan, or losartan for short-term studies; losartan for longer-term studies) monotherapy (Figure). With aliskiren/thiazide diuretic combination therapy, there was a statistically significantly increased risk for hypotension in the short-term studies. This was more frequently reported with aliskiren/thiazide diuretic therapy than with aliskiren monotherapy but not thiazide diuretic monotherapy.

Figure FIGURE.

 Relative risks (RRs) of adverse events of special interest with aliskiren/angiotensin receptor blocker (ARB) combination compared with ARB and aliskiren monotherapy in the short-term studies. CI indicates confidence interval; ND, not determined.

Angioedema.  Angioedema/urticaria events were experienced by a small number of patients. No patient had angioedema/urticaria while receiving combination therapy with aliskiren/ARB in either the short- or longer-term studies, and no patient had angioedema/urticaria with aliskiren/thiazide diuretic combination therapy in the longer-term studies. One patient receiving the aliskiren/thiazide diuretic combination therapy in the short-term studies had mild facial swelling. Angioedema/urticaria events were experienced by a small proportion of patients receiving monotherapy with aliskiren (0.2% in the short-term studies and 0.5% in the longer-term studies), ARBs (0.3% in the short-term studies and 0% in the longer-term studies), or thiazide diuretic (0.2% in the short-term studies and 0.4% in the longer-term studies) (Table IV). Of these events, only 2 were classed as serious (1 in the short-term ARB group and 1 in the longer-term aliskiren 150-mg group).

Table IV.   Adverse Events of Special Interest
(A) Short-Term, Placebo-Controlled Studies
Adverse Event of Special InterestAliskiren Monotherapy (150 mg or 300 mg)
n=2985
Aliskiren (150 mg)
n=1435
Aliskiren (300 mg)
n=1550
Aliskiren/HCTa
n=900
HCTb
n=555
Aliskiren/ Valsartanc
n=564
ARBd
n=1069
Angioedema/urticaria7 (0.2)3 (0.2)4 (0.3)   1 (0.1)1 (0.2)03 (0.3)
Cough31 (1.0)20 (1.4)11 (0.7)11 (1.2)4 (0.7)  2 (0.4)4 (0.4)
Rash8 (0.3)4 (0.3)4 (0.3)3 (0.3)4 (0.7)01 (0.1)
Hypotension61 (2.0)21 (1.5)40 (2.6)42 (4.7)19 (3.4)  16 (2.8)25 (2.3)
Hyperkalemia2 (0.1)1 (0.1)1 (0.1)01 (0.2)00
Peripheral edema24 (0.8)6 (0.4)18 (1.2)9 (1.0)7 (1.3)  1 (0.2)5 (0.5)
Renal dysfunction11 (0.4)7 (0.5)4 (0.3)1 (0.1)0  2 (0.4)2 (0.2)
Diarrhea45 (1.5)18 (1.3)27 (1.7)19 (2.1)10 (1.8)  8 (1.4)17 (1.6)
Gastrointestinal bleeding or ulceration2 (0.1)1 (0.1)1 (0.1)2 (0.2)1 (0.2)01 (0.1)
(B) Longer-Term, Active-Controlled Studies
Adverse Event of Special InterestAliskiren Monotherapy (150 mg and 300 mg)
n=1593
Aliskiren (150 mg)
n=871
Aliskiren
(300 mg)
n=722
HCTe
n=558
Aliskiren/ losartanf
n=155
Losartang
n=154
  1. Abbreviations: ARB, angiotensin receptor blocker; HCT, hydrochlorothiazide. Values are presented as number (percentage) of patients and are summarized according to the treatment to which patients were randomized (excluding regimens using the unlicensed 75 mg and 600 mg doses of aliskiren). aAliskiren/HCT 150/6.25 mg to 300/25 mg. b6.25 to 25 mg. cAliskiren/ valsartan 150/160 mg to 300/320 mg. dLosartan 50 mg, irbesartan 150 mg, or valsartan 80 mg to 320 mg. eHCT 12.5 mg to 25 mg; HCT/amlodipine 25/5 mg to 10 mg (in one study, amlodipine was added to HCT if blood pressure was not controlled to <140/90 mm Hg).22 fAliskiren/losartan 150/50 mg to 300/100 mg. gLosartan 50 mg to 100 mg.

Angioedema/urticaria     8 (0.5)5 (0.6)3 (0.4)2 (0.4)00
Cough62 (3.9)38 (4.4)24 (3.3)22 (3.9)2 (1.3)3 (1.9)
Rash14 (0.9)6 (0.7)8 (1.1)5 (0.9)1 (0.6)1 (0.6)
Hypotension124 (7.8)75 (8.6)49 (6.8)39 (7.0)15 (9.7)8 (5.2)
Hyperkalemia2 (0.1)1 (0.1)1 (0.1)001 (0.6)
Peripheral edema75 (4.7)41 (4.7)34 (4.7)35 (6.3)3 (1.9)2 (1.3)
Renal dysfunction6 (0.4)2 (0.2)4 (0.6)2 (0.4)01 (0.6)
Diarrhea74 (4.6)52 (6.0)22 (3.0)17 (3.0)7 (4.5)9 (5.8)
Gastrointestinal bleeding or ulceration3 (0.2)1 (0.1)2 (0.3)2 (0.4)2 (1.3)1 (0.6)

Cough.  In the short- and longer-term studies, cough was no more common in aliskiren/ARB-treated patients than in those treated with the individual monotherapies. In the short-term studies, 0.4% of patients treated with aliskiren/valsartan combination therapy experienced cough, compared with 1.0% of those treated with aliskiren monotherapy and 0.4% of those treated with ARBs (Table IVA). In the longer-term studies, cough was experienced by 1.3% of patients receiving aliskiren/losartan compared with 3.9% of those receiving aliskiren monotherapy and 1.9% of those receiving losartan monotherapy (Table IVB). Cough was experienced by a slightly greater proportion of patients who received the aliskiren/thiazide diuretic combination (1.2%) than in those who received aliskiren monotherapy (1.0%) or thiazide diuretic monotherapy (0.7%) in the short-term studies, but there was no statistically significant increased risk of the event.

Hyperkalemia.  No patient receiving aliskiren/ARB or aliskiren/HCT combination therapy had hyperkalemia reported as an AE in either the short-term or longer-term studies.

Diarrhea.  During the short- and longer-term studies, diarrhea was experienced by a similar proportion of patients receiving combination treatment to those receiving either of the component monotherapies. In the short-term studies, 1.4% of patients treated with aliskiren/valsartan and 2.1% of those treated with aliskiren/thiazide diuretic had diarrhea compared with 1.5% of patients treated with aliskiren monotherapy, 1.6% of those treated with ARB monotherapy, and 1.8% of those treated with thiazide monotherapy (Table IVA). In the longer-term studies, 4.5% of patients treated with aliskiren/losartan had diarrhea compared with 4.6% of those treated with aliskiren monotherapy and 5.8% of those treated with losartan monotherapy (Table IVB).

Colorectal Findings.  Few patients in any treatment group had colorectal events of interest. In the short-term studies, rectal bleeding or hematochezia was observed in 2 patients receiving aliskiren monotherapy, 1 receiving valsartan monotherapy, and 2 receiving aliskiren/thiazide diuretic. In addition, 1 patient treated with thiazide diuretic monotherapy had erosive gastritis. One of the events (mild rectal bleeding with aliskiren/HCT combination therapy) was suspected possibly to be related to study drug treatment by local investigators. The study drug was not adjusted or discontinued, and no concomitant or non–drug therapies were administered. No patient receiving aliskiren/valsartan therapy had any signs of rectal bleeding or other colorectal events of interest. In the longer-term studies, colorectal events were experienced by 3 patients in the aliskiren monotherapy group (colon adenoma and rectal ulcer [1 patient], diverticular perforation, and erosive duodenitis), 2 patients in the aliskiren/losartan group (gastric ulcer and erosive gastritis), 1 patient treated with losartan monotherapy (duodenal ulcer hemorrhage), and 2 in the thiazide diuretic monotherapy group (colon neoplasm and gastrointestinal carcinoma).

Hypotension.  In the short-term studies, the incidence of hypotension with aliskiren/thiazide diuretic combination therapy (4.7%) was similar to that observed with thiazide diuretic monotherapy (3.4%; RR, 1.36; 95% CI, 0.80–2.32), but significantly greater than that observed with aliskiren monotherapy (2.0%; RR, 2.28, 95% CI, 1.55–3.36). In the longer-term studies, there were no differences in the risk of hypotension between aliskiren/losartan combination therapy and either monotherapy.

Subgroup Analyses

No evidence of an increased risk of AEs with either aliskiren/thiazide diuretic or aliskiren/ARB (valsartan or losartan) combination therapy relative to the individual monotherapies was found for high-risk patient subgroups, including patients 65 years and older, those with diabetes, or those with renal impairment (estimated glomerular filtration rate <60 mL/min/1.73 m2).

Discussion

Principal Findings

Our analysis shows that combination of the direct renin inhibitor aliskiren with the ARBs valsartan or losartan or a thiazide diuretic has similar tolerability to the component monotherapies. Data from 310 patient-years of aliskiren-based combination treatment in short-term studies showed that the safety and tolerability profile of aliskiren/valsartan combination therapy was similar to that of aliskiren, ARB (losartan, irbesartan, or valsartan), and thiazide diuretic monotherapies. These findings were confirmed by data from longer-term studies, which provided an additional 219 patient-years of aliskiren-based combination treatment exposure. In both the short- and longer-term studies, serious AEs and AEs leading to study discontinuation were infrequent, and there was no clustering of events within a particular system organ class.

All AEs of Special Interest

This pooled analysis assessed class-specific AEs previously seen with agents that target the RAS.26,28–31 In addition, evidence of renal dysfunction has been observed previously when RAS blockers have been used with diuretics and in volume-depleted individuals.24,25 Special attention was also paid to gastrointestinal AEs, because diarrhea and symptoms of irritable bowel syndrome have been observed in clinical studies using supratherapeutic aliskiren doses (≥600 mg).7,8,32,33

The incidence of angioedema overall was low, and thus it is difficult to draw firm conclusions from the present analysis. Data from routine post-marketing surveillance will help to clarify the study findings; however, the results are consistent with our findings from a previous analysis of the pooled database.14 Combination therapy with aliskiren was not associated with increased risk of cough compared with monotherapy, either in the short-term or longer-term studies.

Hyperkalemia is a potential concern with agents that target the RAS, particularly for patients with renal dysfunction or diabetes.34 As in the present analysis, data from a 54-week, open-label study in patients with hypertension show a low incidence of serum potassium elevations with an aliskiren/valsartan combination. The incidence of clinically relevant potassium elevations to ≥6 mmol/L was 1.5% and 0% in the subgroups of patients with mild and moderate renal dysfunction, respectively.35

Our analysis suggests that short- and longer-term aliskiren-based combination therapy does not increase the risk of diarrhea compared with aliskiren, ARB (valsartan, irbesartan, or losartan), or thiazide diuretic monotherapy. These findings support original study findings7–11 and our previous analysis of aliskiren monotherapy.14

Limitations

A potential limitation of this analysis was that AEs of special interest were analyzed according to the final treatment regimen to which patients were randomized. Thus, patients could have experienced AEs while taking a different regimen, for example, during titration periods. However, this factor probably overestimates the incidence of AEs with combination therapy and hence does not affect our conclusion that combined therapy is well-tolerated.

Conclusions and Implications of the Findings

Single-pill combinations of aliskiren/valsartan and aliskiren/HCT are now approved treatments for hypertension in the United States. The present safety analysis of more than 12,000 patients in randomized, controlled clinical trials demonstrates that aliskiren in combination with HCT, valsartan, or losartan is well tolerated and has a good safety profile in patients with hypertension, including older individuals and those with additional risk factors such as diabetes. The safety and tolerability profile of aliskiren in combination with an ARB or thiazide diuretic was similar to that of the component monotherapies. Tolerability is an important contributory factor to patient adherence, which can often present a barrier to the long-term achievement of BP goals.36,37 Previous studies have suggested that adherence to ARBs is better than to ACE inhibitors,38–40 possibly reflecting the superior tolerability profile of the ARB class. The results of this analysis and our previous analysis of aliskiren monotherapy14 suggest that the combination of aliskiren with valsartan or losartan, or a thiazide diuretic, are safe therapies for the treatment of patients with hypertension who are likely to need combination therapy to achieve BP control.41,42

Acknowledgments and disclosures:

The authors acknowledge Dr Anil Rustgi and Dr Stanley Hamilton for their participation on the external safety board, and Dr Annette Keith from Oxford PharmaGenesis Ltd for assistance with preparation of the tables and figures for the article. WBW, RB, APK, BFP, and RHR are members of the Aliskiren Safety Monitoring Committee that meet once or twice annually and receive financial remuneration for that role. WBW has received research and grant support from National Institutes of Health and Novartis Pharmaceuticals Corporation and is the president-elect for the American Society of Hypertension. APK has served as a consultant for Novartis Pharmaceuticals Corporation. BFP has received speaker honoraria from Novartis Pharmaceuticals Corporation. RB and RHR declare no further conflicts of interest. AL is an employee of Novartis Pharma AG, Basel, Switzerland, and WC and DLK are employees of Novartis Pharmaceuticals Corporation, East Hanover, NJ; all three are thus eligible for Novartis stock and stock options.

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