Abstract
J Clin Hypertens (Greenwich). 2010;12:765‐775. © 2010 Wiley Periodicals, Inc.
While the safety of renin‐angiotensin system (RAS)–blocking drugs such as angiotensin‐converting enzyme (ACE) inhibitors and angiotensin receptor blockers is well known, less is known about the new direct renin inhibitor aliskiren. The authors pooled data from 12 randomized controlled trials of aliskiren in patients with hypertension and analyzed the incidence and types of adverse events (AEs) and laboratory abnormalities. Studies were characterized as short‐term (≤2 months) placebo‐controlled or long‐term (>2 months) active‐controlled. Relative risks for AEs of particular interest for RAS blockers were calculated. In short‐term studies, AEs occurred in similar proportions of aliskiren 150 mg and 300 mg (33.6% and 31.6%, respectively) and placebo treatment groups (36.8%). In long‐term studies, a lower proportion of patients treated with aliskiren 150 mg and 300 mg had AEs (33.7% and 43.2%, respectively) than those treated with ACE inhibitors (60.1%), angiotensin receptor blockers (53.9%), and thiazide diuretics (48.9%). Events of special interest, including angioedema, hyperkalemia, and diarrhea occurred in similar proportions of patients taking aliskiren, placebo, and comparator agents. In studies of up to 36 weeks, patients treated with aliskiren were significantly less likely to develop cough than those treated with ACE inhibitors. At the registered doses of 150 mg and 300 mg daily, aliskiren has safety and tolerability profiles similar to placebo, other RAS blockers, and diuretics. Cough rates are lower with aliskiren compared with ACE inhibitors.
Aliskiren was the first oral direct renin inhibitor and was approved for the treatment of hypertension at once‐daily doses of 150 mg and 300 mg in 2007. By inhibiting the enzyme renin, aliskiren reduces plasma renin activity (PRA) and prevents the conversion of angiotensinogen to angiotensin (Ang) I, which, in turn, reduces levels of Ang II and aldosterone. 1 Angiotensin‐converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) act at later steps in the pathway and stimulate a reactive increase in PRA. ACE inhibitors also increase levels of Ang I, while ARBs increase both Ang I and Ang II. 1 With long‐term ACE inhibition, Ang I can be converted to Ang II via ACE‐independent mechanisms. 1 A theoretic difference for renin inhibitors is that they may provide more comprehensive inhibition of the renin‐angiotensin system (RAS) compared with ACE inhibitors and ARBs and may have a different safety profile than these agents.
Clinical trials have shown that aliskiren reduces blood pressure (BP) in patients with hypertension when given alone or in combination with other antihypertensive therapies. 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 Moreover, aliskiren has been shown to induce reductions in albuminuria in diabetic nephropathy, 2 B‐type natriuretic peptide levels in heart failure, 3 and left ventricular mass in hypertensive patients with left ventricular hypertrophy. 4 In preregistration clinical trials, the safety profile of aliskiren was similar to that of placebo. 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 However, because RAS blockers have been associated with cough, 12 , 13 angioedema, 12 and hyperkalemia, 14 , 15 post‐approval monitoring of these events has been required for aliskiren.
In 2006, a global safety oversight committee was formed to analyze and review all safety data related to the administration of aliskiren in patients with hypertension and related comorbid populations. The safety data were pooled from all short‐term placebo‐controlled and long‐term active‐controlled aliskiren clinical trials. We report our findings from these data on more than 12,000 patients.
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 March 31, 2009, were included. Studies investigating the single‐pill combination of aliskiren and hydrochlorothiazide (HCT) were excluded. Thirty‐one 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 were excluded because they were not studies of hypertension. Therefore, safety data from 12 randomized double‐blind clinical trials in patients with hypertension were evaluated: 8 short‐term (8‐week) placebo‐controlled studies 7 , 10 , 16 , 17 , 18 , 19 , 20 , 21 and 4 long‐term (26‐ to 52‐week) active‐controlled studies. 4 , 8 , 22 , 23 The current analysis assessed the safety of aliskiren as monotherapy in the registered doses of 150 mg and 300 mg. Most studies enrolled patients with stage 1 or 2 hypertension (seated diastolic BP ≥90 or ≥95 mm Hg and <110 mm Hg); 2 trials enrolled special populations (overweight patients with left ventricular hypertrophy and patients aged 65 years and older with systolic hypertension [seated systolic BP of 140 to <180 mm Hg and diastolic BP <110 mm Hg]). Exclusion criteria were similar across studies and included secondary hypertension, history of severe or uncontrolled cardiovascular diseases, type 1 or uncontrolled type 2 diabetes, and clinically significant hepatic, renal, or endocrine disorders.
AEs: Search Terms
All AEs that occurred during the treatment period of the studies were tabulated. The pooled databases were searched for events of special interest that are related to RAS agents: angioedema/urticaria, cough, rash, hypotension, hyperkalemia, peripheral edema, renal dysfunction, diarrhea, and colorectal events. 12 , 13 , 14 , 15 , 24 , 25 , 26 , 27 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 and 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, gastrointestinal hemorrhage, ulceration, and perforation.
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, irrespective of doses used during any titration period:
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•
In the short‐term placebo‐controlled studies, pooled treatment groups included placebo, aliskiren 150 mg, aliskiren 300 mg, aliskiren and thiazide diuretic, aliskiren and ARB, thiazide diuretic monotherapy, and ARB monotherapy.
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•
In the long‐term active‐controlled studies, the pooled treatment groups included aliskiren monotherapy at all doses, aliskiren 150 mg, aliskiren 300 mg, all aliskiren therapy (monotherapy and combination therapy), ARB monotherapy, aliskiren and ARB, ACE inhibitor monotherapy, and thiazide diuretic monotherapy.
Drug exposure data and all AEs were tabulated according to treatment actually received during any study period. For the events of special interest, pairwise comparisons were performed and relative risks with associated 95% confidence intervals (CIs) were determined for aliskiren monotherapy (individual doses) vs placebo (short‐term studies); aliskiren monotherapy vs thiazide diuretic monotherapy (long‐term studies); and all aliskiren (monotherapy and aliskiren‐based combination therapy) vs ACE inhibitor monotherapy (long‐term studies).
Results
Patients and Exposure
Safety data were available in 12,188 patients: 8862 patients from short‐term placebo‐controlled studies and 3326 patients from the long‐term active‐controlled studies. The exposure to study medication is detailed in Table I.
Table I.
Exposure to Study Drug
| A. Short‐Term Placebo‐Controlled Studies | |||||||
|---|---|---|---|---|---|---|---|
| Placebo n=1555 | Aliskiren 150 mg n=1683 | Aliskiren 300 mg n=1320 | Aliskiren/HCT n=1464 | HCT n=555 | Aliskiren/ARB n=624 | ARB n=1069 | |
| Duration of exposure, d | |||||||
| ≥1 | 1555 (100.0) | 1683 (100.0) | 1320 (100.0) | 1464 (100.0) | 555 (100.0) | 624 (100.0) | 1069 (100.0) |
| ≥14 | 1507 (96.9) | 1640 (97.4) | 1301 (98.6) | 1424 (97.3) | 544 (98.0) | 605 (97.0) | 1054 (98.6) |
| ≥28 | 1432 (92.1) | 1429 (84.9) | 1198 (90.8) | 1394 (95.2) | 533 (96.0) | 591 (94.7) | 1023 (95.7) |
| ≥42 | 1386 (89.1) | 1177 (69.9) | 877 (66.4) | 1385 (94.6) | 524 (94.4) | 581 (93.1) | 996 (93.2) |
| ≥56 | 971 (62.4) | 876 (52.0) | 652 (49.4) | 965 (65.9) | 380 (68.5) | 389 (62.3) | 736 (68.8) |
| ≥70 | 8 (0.5) | 3 (0.2) | 2 (0.2) | 13 (0.9) | 4 (0.7) | 4 (0.6) | 1 (0.1) |
| ≥84 | 1 (0.1) | 0 | 0 | 4 (0.3) | 0 | 1 (0.2) | 0 |
| ≥98 | 0 | 0 | 0 | 1 (0.1) | 0 | 1 (0.2) | 0 |
| Cumulative exposure (patient‐years) | 222.4 | 217.0 | 169.0 | 217.9 | 82.6 | 91.7 | 157.8 |
| B. Long‐Term Active‐Controlled Studies | |||||||
|---|---|---|---|---|---|---|---|
| Aliskiren Alone (All Doses) n=1588 | Aliskiren 150 mg n=1485 | Aliskiren 300 mg n=1297 | All Aliskiren a n=1744 | ARB n=154 | ACE Inhibitor n=865 | HCT n=544 | |
| Duration of exposure, d | |||||||
| ≥1 | 1588 (100.0) | 1485 (100.0) | 1297 (100.0) | 1744 (100.0) | 154 (100.0) | 865 (100.0) | 544 (100.0) |
| ≥14 | 1553 (97.8) | 1413 (95.2) | 1284 (99.0) | 1707 (97.9) | 152 (98.7) | 845 (97.7) | 538 (98.9) |
| ≥28 | 1504 (94.7) | 766 (51.6) | 1248 (96.2) | 1657 (95.0) | 150 (97.4) | 822 (95.0) | 522 (96.0) |
| ≥42 | 1471 (92.6) | 488 (32.9) | 1155 (89.1) | 1635 (93.8) | 149 (96.8) | 803 (92.8) | 506 (93.0) |
| ≥56 | 1427 (89.9) | 324 (21.8) | 991 (76.4) | 1604 (92.0) | 148 (96.1) | 786 (90.9) | 479 (88.1) |
| ≥70 | 1389 (87.5) | 294 (19.8) | 749 (57.7) | 1576 (90.4) | 148 (96.1) | 760 (87.9) | 466 (85.7) |
| ≥84 | 1299 (81.8) | 268 (18.0) | 710 (54.7) | 1565 (89.7) | 148 (96.1) | 663 (76.6) | 430 (79.0) |
| ≥98 | 980 (61.7) | 222 (14.9) | 660 (50.9) | 1543 (88.5) | 146 (94.8) | 430 (49.7) | 328 (60.3) |
| ≥180 | 771 (48.6) | 157 (10.6) | 505 (38.9) | 1475 (84.6) | 137 (89.0) | 277 (32.0) | 256 (47.1) |
| ≥360 | 196 (12.3) | 0 | 4 (0.3) | 369 (21.2) | 0 | 0 | 157 (28.9) |
| Cumulative exposure (patient‐years) | 771.3 | 223.3 | 548.0 | 1157.6 | 99.6 | 309.1 | 300.6 |
Abbreviations: ACE, angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; HCT, hydrochlorothiazide. Data are presented according to treatment actually received at any point during the studies. aAll aliskiren includes patients who received aliskiren as monotherapy or in combination with other antihypertensive agents.
Baseline Patient Characteristics
Baseline characteristics of patients were generally balanced across the pooled treatment groups (Table II). In the short‐term studies, the duration of hypertension and proportion of obese patients were slightly lower in the aliskiren 150‐mg group than in the other treatment groups. In the long‐term studies, the proportion of patients 65 years and older was higher in the aliskiren 150‐mg and ACE inhibitor groups, reflecting the inclusion of a study in patients 65 years and older in the analyses. Body weight and the incidence of obesity were higher in the ARB group than in the other treatment groups because one study, which compared aliskiren 300 mg with losartan 100 mg, enrolled only patients who were overweight.
Table II.
Baseline Characteristics of Patients Included in the Pooled Analysis
| A. Short‐Term Placebo‐Controlled Studies | |||||||
|---|---|---|---|---|---|---|---|
| Baseline Characteristic | Placebo n=1555 | Aliskiren 150 mg n=1246 | Aliskiren 300 mg n=1363 | Aliskiren/HCT n=1464 | HCT n=555 | Aliskiren/ARB n=624 | ARBn=1069 |
| Age, mean ± SD, y | 53.4±11.0 | 53.4±11.3 | 53.5±11.0 | 54.6±11.2 | 55.2±12.2 | 53.4±10.9 | 53.4±10.9 |
| Age group, No. (%) | |||||||
| <65 y | 1314 (84.5) | 1034 (83.0) | 1146 (84.1) | 1177 (80.4) | 415 (74.8) | 525 (84.1) | 901 (84.3) |
| ≥65 y | 241 (15.5) | 212 (17.0) | 217 (15.9) | 287 (19.6) | 140 (25.2) | 99 (15.9) | 168 (15.7) |
| ≥75 y | 53 (3.4) | 34 (2.7) | 40 (2.9) | 44 (3.0) | 21 (3.8) | 14 (2.2) | 26 (2.4) |
| Male, % | 61.2 | 64.0 | 57.7 | 54.1 | 54.4 | 59.6 | 62.3 |
| Race | |||||||
| Caucasian | 999 (64.2) | 661 (53.0) | 985 (72.3) | 1261 (86.1) | 474 (85.4) | 500 (80.1) | 587 (54.9) |
| Black | 159 (10.2) | 86 (6.9) | 142 (10.4) | 62 (4.2) | 31 (5.6) | 74 (11.9) | 129 (12.1) |
| Asian | 318 (20.5) | 452 (36.3) | 157 (11.5) | 39 (2.7) | 12 (2.2) | 8 (1.3) | 311 (29.1) |
| Other | 79 (5.1) | 47 (3.8) | 79 (5.8) | 102 (7.0) | 38 (6.8) | 42 (6.7) | 42 (3.9) |
| BMI, mean ± SD, kg/m2 | 29.3±5.7 | 28.1±5.3 | 29.6±5.8 | 29.4±5.4 | 29.4±5.5 | 30.2±5.6 | 29.2±5.6 |
| Duration of hypertension, No. (mean ± SD), y | 1370 (7.3±6.9) | 1084 (6.6±6.8) | 1180 (7.9±7.4) | 1428 (7.6±7.3) | 537 (7.8±8.0) | 581 (8.0±7.7) | 900 7.4±7.4 |
| Obese (BMI >30 kg/m2), % | 37.2 | 28.3 | 39.8 | 38.0 | 36.8 | 44.7 | 36.5 |
| Diabetes, % | 7.9 | 7.9 | 9.8 | 7.7 | 7.6 | 10.3 | 8.9 |
| Baseline renal function (eGFR), No. (%) | |||||||
| <60 mL/min/1.73 m2 | 47 (3.0) | 37 (3.0) | 41 (3.0) | 61 (4.2) | 20 (3.6) | 18 (2.9) | 30 (2.8) |
| ≥60 to <90 mL/min/1.73 m2 | 720 (46.3) | 557 (44.7) | 668 (49.0) | 807 (55.1) | 304 (54.8) | 324 (51.9) | 468 (43.8) |
| ≥90 mL/min/1.73 m2 | 781 (50.2) | 652 (52.3) | 641 (47.0) | 596 (40.7) | 231 (41.6) | 270 (43.3) | 566 (52.9) |
| Data not available | 7 (0.5) | 0 | 13 (1.0) | 0 | 0 | 12 (1.9) | 5 (0.5) |
| Sitting SBP, mean ± SD, mm Hg | 153.0±12.4 | 153.0±12.0 | 153.5±11.8 | 153.7±12.3 | 153.8±12.1 | 153.0±12.4 | 153.5±11.8 |
| Sitting DBP, mean ± SD, mm Hg | 99.6±3.9 | 99.3±3.7 | 99.7±3.8 | 99.2±3.6 | 99.2±3.4 | 99.7±4.0 | 99.7±4.0 |
| B. Long‐Term Active‐Controlled Studies | |||||||
|---|---|---|---|---|---|---|---|
| Baseline Characteristic | Aliskiren Alone (All Doses) n=1594 | Aliskiren 150 mg n=871 | Aliskiren 300 mg n=723 | All Aliskiren a n=1749 | ARBn=154 | ACE Inhibitor n=866 | HCTn=557 |
| Age, mean ± SD, y | 60.1±12.2 | 63.1±12.6 | 56.6±10.7 | 60.0±12.0 | 59.1±11.0 | 62.9±13.0 | 55.7±10.9 |
| Age group, No. (%) | |||||||
| <65 y | 903 (56.6) | 356 (40.9) | 547 (75.7) | 1011 (57.8) | 101 (65.6) | 359 (41.5) | 430 (77.2) |
| ≥65 y | 691 (43.4) | 515 (59.1) | 176 (24.3) | 738 (42.2) | 53 (34.4) | 507 (58.5) | 127 (22.8) |
| ≥75 y | 179 (11.2) | 156 (17.9) | 23 (3.2) | 184 (10.5) | 8 (5.2) | 160 (18.5) | 19 (3.4) |
| Male, % | 54.1 | 50.9 | 58.1 | 56.2 | 76.6 | 53.5 | 56.0 |
| Race | |||||||
| Caucasian | 1403 (88.0) | 696 (79.9) | 707 (97.8) | 1550 (88.6) | 145 (94.2) | 704 (81.3) | 552 (99.1) |
| Black | 118 (7.4) | 117 (13.4) | 1 (0.1) | 119 (6.8) | 2 (1.3) | 105 (12.1) | 0 |
| Asian | 37 (2.3) | 32 (3.7) | 5 (0.7) | 38 (2.2) | 0 | 31 (3.6) | 4 (0.7) |
| Other | 36 (2.3) | 26 (3.0) | 10 (1.4) | 42 (2.4) | 7 (4.5) | 26 (3.0) | 1 (0.2) |
| BMI, mean ± SD, kg/m2 | 29.7±5.3 | 29.9±5.8 | 29.4±4.6 | 29.8±5.2 | 30.8±4.1 | 30.4±6.3 | 29.1±4.8 |
| Duration of hypertension, mean ± SD, y | 9.0±8.7 | 9.8±9.4 | 8.1±7.6 | 9.3±8.9 | 12.3±9.1 | 9.8±9.1 | 6.9±6.8 |
| Obese, % | 41.3 | 41.9 | 40.7 | 42.7 | 50.0 | 46.2 | 33.8 |
| Diabetes, % | 14.9 | 16.1 | 13.4 | 16.0 | 22.1 | 15.7 | 10.8 |
| Baseline renal function (eGFR), No. (%) | |||||||
| <60 mL/min/1.73 m2 | 138 (8.7) | 105 (12.1) | 33 (4.6) | 150 (8.6) | 13 (8.4) | 105 (12.1) | 38 (6.8) |
| ≥60 to <90 mL/min/1.73 m2 | 816 (51.2) | 394 (45.2) | 422 (58.4) | 901 (51.5) | 89 (57.8) | 377 (43.5) | 335 (60.1) |
| ≥90 mL/min/1.73 m2 | 637 (40.0) | 370 (42.5) | 267 (36.9) | 691 (39.5) | 49 (31.8) | 382 (44.1) | 184 (33.0) |
| Data not available | 3 (0.2) | 2 (0.2) | 1 (0.1) | 7 (0.4) | 3 (1.9) | 2 (0.2) | 0 |
| Sitting SBP, mean ± SD, mm Hg | 153.3±12.0 | 154.1±11.6 | 152.4±12.4 | 152.5±12.4 | 146.3±13.4 | 154.1±11.4 | 154.3±11.0 |
| Sitting DBP, mean ± SD, mm Hg | 94.2±8.8 | 91.9±9.8 | 96.8±6.7 | 93.6±9.0 | 89.1±10.1 | 92.3±9.4 | 99.0±3.4 |
Abbreviations: ACE, angiotensin‐converting enzyme; 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 presented according to the treatment group to which patients were randomized, irrespective of doses used during any titration periods. Three treatment groups are not presented in Table IIA: nonapproved 75‐mg and 600‐mg doses of aliskiren and ARB/HCT combination therapy. One treatment group is not presented in Table IIB: aliskiren/ARB combination therapy. aAll aliskiren includes patients who have received aliskiren as monotherapy or in combination with other antihypertensive agents.
Serious AEs
Serious AEs occurred in a similar proportion of patients who received short‐term treatment with aliskiren (150 mg=0.4%; 300 mg=0.5%) compared with those who received placebo (0.7%). In the long‐term studies, the incidence of serious AEs with aliskiren monotherapy (3.4%) was greater than that observed with ACE inhibitor (2.4%) or thiazide diuretic monotherapy (1.7%) and lower than that with ARB monotherapy (8.4%). The serious AEs did not cluster within any particular system organ class. The most frequently reported events in patients receiving long‐term aliskiren monotherapy were atrial fibrillation (5 patients [0.3%]) and diverticulitis (3 patients [0.2%]).
All AEs
In the short‐term studies, AEs were reported by similar proportions of patients who received aliskiren 150 mg (33.6%), aliskiren 300 mg (31.6%), and placebo (36.8%). Long‐term treatment was associated with AEs in 33.7% of patients receiving aliskiren 150 mg and 43.2% of those receiving aliskiren 300 mg, lower proportions than those receiving ACE inhibitor (60.1%), ARB (53.9%), or thiazide diuretic (48.9%) therapy. Discontinuations due to AEs were uncommon (short‐term studies: ≤1.4% for both aliskiren doses and 2.6% for placebo; long‐term studies: 3.2% for aliskiren 150 mg and 1.7% for aliskiren 300 mg). A greater proportion of patients discontinued due to AEs when treated with ACE inhibitors (6.9%) or ARBs (6.5%) in the long‐term studies, while a similar proportion to those treated with aliskiren (4.3% overall) discontinued long‐term thiazide diuretic therapy (3.3%).
AEs of Special Interest
During the short‐term trials, each of the AEs of special interest occurred in fewer than 3% of patients in each aliskiren treatment group, a similar proportion to those who received placebo (TableIII). There were no statistically significant increases in the relative risk of any of the specific AEs with aliskiren 150‐mg and 300‐mg doses compared with placebo (Figure 1). In the long‐term trials, hypotension (7.6%) and peripheral edema (4.8%) were the most frequently reported events of special interest on aliskiren (Table III), and had incidences comparable with those for ARBs, ACE inhibitors, and thiazide diuretics (4.5%–9.1% for hypotension and 1.3%–6.1% for peripheral edema).
Table III.
Adverse Events of Special Interest
| A. Short‐Term Placebo‐Controlled Studies | |||||||
|---|---|---|---|---|---|---|---|
| Adverse Event Of Special Interest | Placebo n=1555 | Aliskiren 150 mg n=1246 | Aliskiren 300 mg n=1363 | Aliskiren/HCT n=1464 | HCT n=555 | Aliskiren/ARB n=624 | ARB n=1069 |
| Angioedema/urticaria | 8 (0.5) | 2 (0.2) | 4 (0.3) | 1 (0.1) | 1 (0.2) | 0 | 3 (0.3) |
| Cough | 11 (0.7) | 18 (1.4) | 10 (0.7) | 20 (1.4) | 4 (0.7) | 3 (0.5) | 4 (0.4) |
| Rash | 6 (0.4) | 3 (0.2) | 3 (0.2) | 3 (0.2) | 4 (0.7) | 0 | 1 (0.1) |
| Hypotension | 34 (2.2) | 16 (1.3) | 37 (2.7) | 54 (3.7) | 19 (3.4) | 16 (2.6) | 25 (2.3) |
| Hyperkalemia | 1 (0.1) | 0 | 1 (0.1) | 0 | 1 (0.2) | 0 | 0 |
| Peripheral edema | 12 (0.8) | 6 (0.5) | 18 (1.3) | 13 (0.9) | 7 (1.3) | 1 (0.2) | 5 (0.5) |
| Renal dysfunction | 2 (0.1) | 7 (0.6) | 3 (0.2) | 1 (0.1) | 0 | 2 (0.3) | 2 (0.2) |
| Diarrhea | 19 (1.2) | 18 (1.4) | 27 (2.0) | 24 (1.6) | 10 (1.8) | 10 (1.6) | 17 (1.6) |
| Gastrointestinal bleeding or ulceration | 2 (0.1) | 1 (0.1) | 1 (0.1) | 3 (0.2) | 1 (0.2) | 1 (0.2) | 1 (0.1) |
| B. Long‐Term Active‐Controlled Studies | |||||||
|---|---|---|---|---|---|---|---|
| Adverse Event of Special Interest | Aliskiren Alone (All Doses) n=1594 | Aliskiren 150 mg n=871 | Aliskiren 300 mg n=723 | All Aliskiren a n=1749 | ARB n=154 | ACE Inhibitor n=866 | HCT n=557 |
| Angioedema/urticaria | 7 (0.4) | 4 (0.5) | 3 (0.4) | 8 (0.5) | 0 | 4 (0.5) | 2 (0.4) |
| Cough | 62 (3.9) | 38 (4.4) | 24 (3.3) | 64 (3.7) | 3 (1.9) | 104 (12.0) | 22 (3.9) |
| Rash | 14 (0.9) | 6 (0.7) | 8 (1.1) | 15 (0.9) | 1 (0.6) | 4 (0.5) | 5 (0.9) |
| Hypotension | 121 (7.6) | 73 (8.4) | 48 (6.6) | 135 (7.7) | 7 (4.5) | 79 (9.1) | 36 (6.5) |
| Hyperkalemia | 2 (0.1) | 1 (0.1) | 1 (0.1) | 2 (0.1) | 1 (0.6) | 2 (0.2) | 0 |
| Peripheral edema | 76 (4.8) | 41 (4.7) | 35 (4.8) | 79 (4.5) | 2 (1.3) | 34 (3.9) | 34 (6.1) |
| Renal dysfunction | 6 (0.4) | 2 (0.2) | 4 (0.6) | 6 (0.3) | 1 (0.6) | 3 (0.3) | 2 (0.4) |
| Diarrhea | 74 (4.6) | 52 (6.0) | 22 (3.0) | 81 (4.6) | 9 (5.8) | 33 (3.8) | 17 (3.1) |
| Gastrointestinal tumors, ulceration or perforation | 3 (0.2) | 1 (0.1) | 2 (0.3) | 5 (0.3) | 1 (0.6) | 2 (0.2) | 2 (0.4) |
Abbreviations: ACE, angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; HCT, hydrochlorothiazide. Data are number (%) of patients. aAll aliskiren includes patients who have received aliskiren as monotherapy or in combination with other antihypertensive agents. Data are presented according to the treatment group to which patients were randomized, irrespective of doses used during any titration periods.
Figure 1.
Relative risks of adverse events of special interest with aliskiren 150‐mg or 300‐mg monotherapy compared with placebo in the short‐term studies. Relative risks were calculated using pairwise comparisons with placebo. CI indicates confidence interval; ND, not defined; RR, relative risk.
Angioedema. In short‐term studies, the incidence of angioedema/urticaria was lower in patients receiving aliskiren 150 mg (0.2%) and aliskiren 300 mg (0.3%) than in the placebo group (0.5%; relative risk [RR], 0.31; 95% CI, 0.07–1.47 for 150 mg; RR, 0.57; 95% CI, 0.17–1.89 for 300 mg; Table III); with aliskiren treatment 2 of 6 of these events were angioedema compared with 4 of 8 with placebo. In the long‐term studies, the incidence of angioedema/urticaria associated with aliskiren monotherapy was low (0.4%) and similar to that with ACE inhibitor, ARB, or thiazide diuretic monotherapy (0.0%–0.5%; Table III). The proportion of patients with angioedema relative to urticaria was lower in the aliskiren groups (57%) than in the ACE inhibitor group (75%). No aliskiren‐treated patients in the short‐term trials and only one in the long‐term trials (150 mg) had a serious angioedema event. No patient required hospitalization for angioedema.
Cough. Cough was not significantly different for aliskiren vs placebo. In the long‐term studies, a greater proportion of patients treated with ACE inhibitor monotherapy had cough (12.0%) compared with all other monotherapies (Table III). In addition, the risk of cough with aliskiren was significantly lower than with ACE inhibitors in the 26‐week (RR, 0.43; 95% CI, 0.25–0.74) and 36‐week (RR, 0.32; 95% CI, 0.19–0.52; Figure 2) studies included in the analysis.
Figure 2.
Kaplan–Meier analysis of time to first event for cough during the 36‐week study. Time to the first occurrence of cough was analyzed using Cox proportional hazards regression with randomized treatment included as a fixed effect. ACE indicates angiotensin‐converting enzyme.
Hyperkalemia
In short‐term studies, no patient treated with aliskiren 150 mg and only one treated with aliskiren 300 mg had hyperkalemia (Table III). The incidence of serum potassium elevations to >5.5 mEq/L at any visit during the double‐blind treatment period was generally low on aliskiren and similar to that observed with placebo, ARB, and thiazide diuretic monotherapies (Table IV). During long‐term treatment, the incidence of potassium levels >5.5 mEq/L with aliskiren 300 mg was higher (5.7%) than that in the other treatment groups (1.9%–3.7%; Table IV). The incidence of potassium levels >5.5 mEq/L with aliskiren monotherapy (all doses combined) was similar to that with ARB monotherapy (3.6% vs 3.3%, respectively) (Table IV).
Table IV.
Prespecified Laboratory Abnormalities
| A. Short‐Term Placebo‐Controlled Studies | |||||||
|---|---|---|---|---|---|---|---|
| Laboratory Variable | Placebo n=1555 | Aliskiren 150 mg n=1246 | Aliskiren 300 mg n=1363 | Aliskiren/HCT n=1464 | HCT n=555 | Aliskiren/ARB n=624 | ARB n=1069 |
| Potassium level | n=1455 | n=1167 | n=1266 | n=1171 | n=445 | n=588 | n=1034 |
| <3.5 mEq/L | 41 (2.8) | 12 (1.0) | 19 (1.5) | 21 (1.8) | 14 (3.1) | 13 (2.2) | 26 (2.5) |
| >5.5 mEql/L | 19 (1.3) | 10 (0.9) | 20 (1.6) | 6 (0.5) | 4 (0.9) | 20 (3.4) | 7 (0.7) |
| ≥6.0 mEq/L | 7 (0.5) | 3 (0.3) | 7 (0.6) | 1 (0.1) | 1 (0.2) | 2 (0.3) | 5 (0.5) |
| ≥7.0 mEq/L | 4 (0.3) | 0 | 3 (0.2) | 0 | 0 | 2 (0.3) | 2 (0.2) |
| BUN | n=1385 | n=1098 | n=1195 | n=1437 | n=549 | n=599 | n=922 |
| >40 mg/dL | 0 | 0 | 2 (0.2) | 0 | 0 | 0 | 1 (0.1) |
| Creatinine level | n=1507 | n=1219 | n=1321 | n=1437 | n=549 | n=599 | n=1048 |
| >2.0 mg/dL | 0 | 0 | 4 (0.3) | 0 | 0 | 4 (0.7) | 2 (0.2) |
| eGFR | n=1507 | n=1219 | n=1321 | n=1437 | n=549 | n=599 | n=1048 |
| <30 mL/min/1.73 m2 | 0 | 0 | 1 (0.1) | 0 | 0 | 2 (0.3) | 1 (0.1) |
| B. Long‐Term Active‐Controlled Studies | |||||||
|---|---|---|---|---|---|---|---|
| Laboratory Variable | Aliskiren Alone (All Doses) n=1594 | Aliskiren 150 mg n=871 | Aliskiren 300 mg n=723 | All Aliskiren a n=1749 | ARB n=154 | ACE inhibitor n=866 | HCT n=557 |
| Potassium level | n=1552 | n=849 | n=703 | n=1705 | n=153 | n=847 | n=537 |
| <3.5 mEq/L | 54 (3.5) | 37 (4.4) | 17 (2.4) | 62 (3.6) | 11 (7.2) | 39 (4.6) | 96 (17.9) |
| >5.5 mEq/L | 56 (3.6) | 16 (1.9) | 40 (5.7) | 61 (3.6) | 5 (3.3) | 16 (1.9) | 20 (3.7) |
| ≥6.0 mEq/L | 25 (1.6) | 7 (0.8) | 18 (2.6) | 26 (1.5) | 1 (0.7) | 4 (0.5) | 10 (1.9) |
| ≥7.0 mEq/L | 5 (0.3) | 0 | 5 (0.7) | 5 (0.3) | 1 (0.7) | 0 | 3 (0.6) |
| BUN | n=1552 | n=849 | n=703 | n=1705 | n=153 | n=848 | n=537 |
| >40 mg/dL | 10 (0.6) | 6 (0.7) | 4 (0.6) | 10 (0.6) | 2 (1.3) | 6 (0.7) | 4 (0.7) |
| Creatinine level | n=1552 | n=849 | n=703 | n=1705 | n=153 | n=848 | n=537 |
| >2.0 mg/dL | 4 (0.3) | 2 (0.2) | 2 (0.3) | 5 (0.3) | 1 (0.7) | 4 (0.5) | 0 |
| eGFR | n=1552 | n=849 | n=703 | n=1705 | n=153 | n=848 | n=537 |
| <30 mL/min/1.73 m2 | 5 (0.3) | 3 (0.4) | 2 (0.3) | 6 (0.4) | 2 (1.3) | 2 (0.2) | 0 |
Abbreviations: ACE, angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; HCT, hydrochlorothiazide. Data are number (%) of patients. Data are presented according to the treatment group to which patients were randomized, irrespective of doses used during any titration periods. aAll aliskiren includes patients who received aliskiren as monotherapy or in combination with other antihypertensive agents.
Diarrhea. Analysis by individual aliskiren monotherapy dose demonstrated no significant increase in diarrhea compared with placebo for patients receiving aliskiren 150 mg (RR, 1.18; 95% CI, 0.62–2.24) or 300 mg (RR, 1.62; 95% CI, 0.91–2.90). In the long‐term studies, there were no notable differences in the relative risk of diarrhea with aliskiren treatment (monotherapy or aliskiren‐based combination therapy) compared with ACE inhibitor monotherapy (26‐week study: RR, 1.92; 95% CI, 0.94–3.94; 36‐week study: RR, 1.38; 95% CI, 0.81–2.35) or thiazide diuretic monotherapy (RR, 0.92; 95% CI, 0.47–1.81).
No patient receiving short‐term treatment with aliskiren 150 mg or 300 mg discontinued due to diarrhea and only 6 of 1594 patients (0.4%) who received long‐term aliskiren monotherapy discontinued because of diarrhea.
Colorectal Findings. In the short‐term studies, one patient in each of the 150‐mg and 300‐mg aliskiren groups and 2 patients in the placebo group had rectal bleeding or hematochezia. There was no evidence for an increased risk of gastrointestinal bleeding or ulceration with aliskiren treatment over placebo in the short‐term studies (RR, 0.62; 95% CI, 0.06–6.87 for aliskiren 150 mg and RR, 0.57; 95% CI, 0.05–6.28 for aliskiren 300 mg). In the long‐term studies, one patient in the aliskiren 150‐mg group had a rectal ulcer and colonic adenoma; in the aliskiren 300 mg group, one patient had diverticular perforation and one had erosive duodenitis.
Discussion
Principal Findings
Our results indicate that based on the published data, aliskiren, a direct renin inhibitor, has short‐term safety findings similar to placebo and long‐term safety findings that are similar or superior to that of other antihypertensive therapies. Data from nearly 400 patient‐years of aliskiren treatment in short‐term studies showed that general safety and tolerability as well as serious AEs were similar to placebo (III, IV) at the doses of 150 mg and 300 mg. In addition, data from more than 750 patient‐years of aliskiren exposure confirmed the tolerability of aliskiren in long‐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.
AEs of Special Interest
Prior studies of antihypertensive therapies that target the RAS have shown some class‐specific AEs, including angioedema, cough, and hyperkalemia. 14 , 24 , 25 , 26 , 27 The pooled database was searched specifically for these terms as well as renal dysfunction, an AE observed primarily when RAS blockers are used with diuretics or in volume‐depleted individuals. 12 , 13 In addition, special attention was paid to gastrointestinal AEs, as diarrhea and symptoms of “irritable bowel syndrome” have been observed in clinical studies using aliskiren doses of ≥600 mg. 1 , 5 , 6 , 28
Angioedema. The risk of angioedema and/or urticaria for aliskiren was similar to placebo in the short‐term studies (Figure 1, Table III ). The incidence of angioedema with aliskiren treatment in the long‐term studies was low (0.4%) and similar to other active treatment groups. Of note, just one case of angioedema was reported as a serious AE. When associated with ACE inhibitor treatment, angioedema that occurs during the first 30 days of exposure 25 is related to elevated bradykinin levels. 29 Theoretically, aliskiren should not confer a risk of angioedema because, unlike ACE inhibitors, it has no known effect on bradykinin metabolism. Since aliskiren decreases levels of Ang I, a competitive substrate for ACE degradation of bradykinin, aliskiren might actually lower bradykinin levels. 30 Our results are consistent with this hypothesis; however, given the low absolute incidence of angioedema, ongoing post‐marketing surveillance will be necessary to confirm these findings. Of note, a woman who had life‐threatening angioedema following treatment with an ACE inhibitor did not experience subsequent angioedema episodes when treated with long‐term aliskiren. 30
Cough. There was no evidence of an association of aliskiren with cough either in the short‐term or long‐term studies (Figure 1, Table III ). ACE inhibitor treatment was associated with a significantly greater development of cough compared with aliskiren (Figure 2 ), consistent with an incidence in the range of 6% to 20% from prior studies. 24 , 31 ACE inhibitor–induced cough is of clinical importance because it often necessitates drug discontinuation. A study of 892 patients receiving an ACE inhibitor in clinical practice found that approximately 9.6% of black patients and 2.6% of non‐black patients discontinued their medication due to persistent cough. 32 Lack of cough during aliskiren treatment is consistent with the lack of effect of direct renin inhibition on the metabolism of bradykinin, the accumulation of which is central to the development of ACE inhibitor–induced cough. 31 , 32
Hyperkalemia and Renal Dysfunction. The risk of hyperkalemia on aliskiren was similar to placebo in the short‐term studies and to the other antihypertensive therapies in the long‐term trials (Figure 1, III, IV ). The incidence rates of mild hyperkalemia (>5.5 mEq/L but <6.0 mEq/L) were higher when aliskiren was combined with ARBs (Table IV).
Development of renal dysfunction was exceedingly low in all aliskiren groups both in the short‐term placebo‐controlled studies as well as the long‐term active‐controlled studies (Table IV). While this finding is reassuring, since most patients in these trials lacked significant renal insufficiency or volume depletion at baseline, our data might not be representative of a higher‐risk population.
Gastrointestinal Disorders. Our analysis confirmed that there was no increased risk of diarrhea compared with placebo in patients receiving 150 mg and 300 mg of aliskiren (Table III). In addition, the incident rates of diarrhea were similar for both doses of aliskiren to the comparator agents used in the long‐term studies (Table III). These findings support original study findings 5 , 6 , 7 , 8 , 9 demonstrating that aliskiren did not increase rates of diarrhea until doses of ≥600 mg were used.
The rates of development of other gastrointestinal disorders including ulcers and polyps were similar among the doses of aliskiren and placebo in the short‐term studies and aliskiren and the comparator agents in the long‐term trials (Table III).
Conclusions and Implications of the Research Findings
The present safety analysis of more than 12,000 patients in controlled clinical trials with similar patient populations demonstrates that aliskiren at doses of 150 mg or 300 mg exhibits an excellent safety profile in patients with hypertension. The safety and tolerability profile of aliskiren was similar to that of placebo and ARBs and superior to ACE inhibitors because of the observed lack of association with cough. These findings suggest that aliskiren will be an effective agent for the treatment of hypertension since tolerability of antihypertensive agents is an important determinant of patient adherence to long‐term drug treatment. 33 , 34 In fact, adherence to ARBs has been shown to be better than to ACE inhibitors, 35 , 36 , 37 likely reflecting the superior tolerability profile of the ARB class. 38 , 39 Our results suggest that, based on the published data, aliskiren represents a well‐tolerated therapeutic option for patients with hypertension. Ongoing studies of aliskiren in other patient groups (eg, those who have type 2 diabetes with additional high cardiovascular or renal risk factors and those 50 years and older) will provide further data on tolerability. 2 , 40
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 (Oxford PharmaGenesis Ltd) for assistance with preparation of the tables, figures, and references for this article. Sources of funding were provided by Novartis Pharmaceuticals Corporation, East Hanover, NJ.
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