Background
Methods
Search strategy and selection criteria
Inclusion and exclusion criteria
Data extraction
Data analysis
Evaluation of quality of included studies
Patient and public involvement
Results
Eligible studies
Antihypertensive effects
BP reduction
Outcome | No. of SRs | No. of original studies | No. of cases/ controls | Follow-up range (weeks) | Estimate (95%CI) | P- value | 95%PI | I2(P*) | Egger’s P value |
---|---|---|---|---|---|---|---|---|---|
msDBP | |||||||||
aliskiren75mg vs placebo | 1 | 5 | 821/279 | 8–13 | − 2.05 [− 3.13,-0.96] | < 0.001 | [− 3.81,-0.28] | 0%(0.73) | 0.043 |
aliskiren150mg vs placebo | 1 | 12 | 2665/1118 | 8–26 | −3.19 [−4.02, -2.37] | < 0.001 | [−5.57,-0.82] | 47%(0.04) | 0.798 |
aliskiren300mg vs placebo | 1 | 10 | 2193/808 | 8–26 | −4.51 [−5.27, −3.76] | < 0.001 | [− 5.97, − 3.06] | 17%(0.29) | 0.359 |
aliskiren600mg vs placebo | 1 | 2 | 296/97 | 8 | −5.86 [−7.73, -3.99] | < 0.0001 | NA | 0%(0.57) | NA |
aliskiren vs ARBs (low dose) | 2 | 4 | 648/532 | 4–8 | 0.07 [−0.94,1.09] | 0.89 | [−2.15,2.30] | 0%(0.48) | 0.12 |
aliskiren vs ARBs (low to high dose) | 2 | 5 | 923/944 | 8–12 | −0.25 [−2.32,1.82] | 0.81 | [−7.82,7.31] | 82% (0.0002) | 0.272 |
aliskiren vs ARBs (high dose) | 2 | 3 | 241/122 | 8 | −0.65 [−2.52, 1.23] | 0.5 | [−12.79,11.49] | 0%(0.89) | 0.293 |
aliskiren vs ACEIs | 2 | 3 | 796/786 | ≥8 | −1.19[− 1.99, −0.38] | 0.004 | [−6.42,4.05] | 0%(0.53) | 0.687 |
aliskiren vs amlodipine | 1 | 1 | 203/181 | 8 | 3.63 [1.85,5.41] | < 0.0001 | NA | NA | NA |
aliskiren vs HCTZ | 1 | 1 | 183/176 | 8 | −0.9 [−2.56,0.76] | 0.29 | NA | NA | NA |
aliskiren vs atenolol | 1 | 1 | 231/231 | 12 | 2.4 [0.74,4.06] | 0.004 | NA | NA | NA |
Aliskiren150mg vs 75 mg | 1 | 5 | 830/824 | 8–13 | −0.8 [−1.58,-0.03] | 0.04 | [−2.06,0.04] | 0%(0.45) | 0.944 |
aliskiren300mg vs 150 mg | 1 | 10 | 2193/2195 | 8–26 | −1.75 [−2.31, − 1.20] | < 0.001 | [− 2.88,-0.63] | 20%(0.26) | 0.584 |
aliskiren600mg vs 300 mg | 1 | 2 | 296/296 | 8 | −0.68[−2.03,0.67] | 0.449 | NA | 33%(0.22) | NA |
msSBP | |||||||||
aliskiren75mg vs placebo | 1 | 5 | 821/279 | 8–13 | −2.97[−4.76, -1.18] | 0.001 | [−5.88,-0.66] | 0%(0.57) | 0.253 |
aliskiren150mg vs placebo | 1 | 12 | 2665/1121 | 8–26 | −5.93[−6.94, -4.91] | < 0.001 | [−7.93,-3.92] | 17%(0.28) | 0.674 |
aliskiren300mg vs placebo | 1 | 10 | 2199/810 | 8–26 | −7.91 [−9.15, −6.67] | < 0.001 | [−10.48,-5.33] | 22%(0.24) | 0.693 |
aliskiren600mg vs placebo | 1 | 2 | 296/97 | 8 | −11.35[− 14.43,-8.27] | < 0.00001 | NA | 0%(0.62) | NA |
aliskiren vs ARBs (low dose) | 2 | 4 | 648/532 | 4–8 | 1.25 [−0.29,2.78] | 0.111 | [−2.57,5.06] | 6%(0.36) | 0.661 |
aliskiren vs ARBs (low to high dose) | 2 | 5 | 923/944 | 8–12 | −1.19[−4.09, 1.70] | 0.42 | [−11.46,9.08] | 77% (0.002) | 0.242 |
aliskiren vs ARBs (high dose) | 2 | 3 | 241/122 | 8 | 0.24 [−2.29, 2.76] | 0.85 | [−16.10,16.57] | 0%(0.65) | 0.841 |
aliskiren vs ACEIs | 2 | 4 | 1253/1230 | ≥8 | −2.37[−3.48, −1.26] | < 0.0001 | [−4.83,0.04] | 0%(0.59) | 0.123 |
aliskiren vs amlodipine | 1 | 1 | 203/181 | 8 | 5.67 [2.86,8.48] | < 0.0001 | NA | NA | NA |
aliskiren vs HCTZ | 1 | 1 | 183/176 | 8 | −1.4 [−4.04,1.24] | 0.3 | NA | NA | NA |
aliskiren vs atenolol | 1 | 1 | 231/231 | 12 | −0.08 [−3.02,2.86] | 0.96 | NA | NA | NA |
aliskiren150mg vs 75 mg | 1 | 5 | 830/821 | 8–13 | −1.89 [−3.34, −0.43] | 0.011 | [−5.37,1.59] | 23%(0.27) | 0.872 |
aliskiren300mg vs 150 mg | 1 | 10 | 2199/2195 | 8–26 | −2.57 [−3.72, −1.42] | < 0.0001 | [− 5.87,0.73] | 52%(0.03) | 0.921 |
aliskiren600mg vs 300 mg | 1 | 2 | 296/296 | 8 | −0.61 [−2.78, 1.56] | 0.581 | NA | 0%(0.60) | NA |
BP response rate
Outcome | No.of SRs | No.of original studies | No.of cases/ controls | Follow-up range (weeks) | Estimate (95%CI) | P- value | 95%PI | I2(P*) | Egger’s P value |
---|---|---|---|---|---|---|---|---|---|
BP response rate | |||||||||
aliskiren 75 mg vs placebo | 2 | 2 | 292/291 | 8 | 1.41 [1.03–1.94] | 0.03 | NA | 62%(0.11) | NA |
aliskiren150mg vs placebo | 2 | 3 | 460/451 | 8 | 1.42 [1.16–1.75] | 0.001 | [0.19–10.87] | 43%(0.17) | 0.008 |
aliskiren300mg vs placebo | 2 | 7 | 1443/1480 | 8 | 1.65 [1.46–1.85] | < 0.001 | [1.17–2.35] | 49%(0.07) | 0.167 |
aliskiren vs ARBs (low dose) | 2 | 2 | 479/361 | 4–8 | 0.92 [0.81–1.04] | 0.16 | NA | 0%(0.89) | NA |
aliskiren vs ARBs (low to high dose) | 2 | 2 | 543/570 | 8–12 | 0.99 [0.90–1.09] | 0.88 | NA | 0%(0.51) | NA |
aliskiren vs ARBs (high dose) | 1 | 1 | 175/60 | 8 | 1.07 [0.86–1.33] | 0.52 | NA | NA | NA |
aliskiren vs ACEIs | 1 | 1 | 414/418 | 8–26 | 1.10 [0.99–1.24] | 0.09 | NA | NA | NA |
aliskiren vs amlodipine | 1 | 2 | 513/492 | 8–32 | 0.77[0.69–0.85] | < 0.00001 | NA | 0% (0.37) | NA |
aliskiren vs HCTZ | 1 | 1 | 180/173 | 8 | 1.08 [0.92–1.28] | 0.34 | NA | NA | NA |
aliskiren vs atenolol | 1 | 1 | 230/230 | 12 | 0.84[0.74–0.95] | 0.007 | NA | NA | NA |
BP control rate | |||||||||
aliskiren 75 mg vs placebo | 2 | 1 | 177/176 | 8 | 1.30 [0.95–1.77] | 0.1 | NA | NA | NA |
aliskiren150mg vs placebo | 2 | 3 | 475/666 | 8 | 1.51 [1.06–2.16] | 0.02 | [0.03–76.62] | 62%(0.07) | 0.084 |
aliskiren300mg vs placebo | 2 | 6 | 1276/1288 | 8 | 1.62 [1.10–2.38] | 0.01 | [0.41–6.36] | 90% (< 0.00001) | 0.741 |
aliskiren vs ARBs (low to high dose) | 2 | 5 | 919/921 | 8–12 | 1.05 [0.89–1.23] | 0.57 | [0.68–1.62] | 37%(0.18) | 0.357 |
aliskiren vs ARBs (high dose) | 1 | 1 | 175/60 | 8 | 1.01 [0.72–1.43] | 0.93 | NA | NA | NA |
aliskiren vs ACEIs | 1 | 1 | 414/418 | 8–26 | 1.12 [0.96–1.30] | 0.15 | NA | NA | NA |
aliskiren vs amlodipine | 1 | 1 | 201/179 | 8 | 0.72 [0.57–0.91] | 0.006 | NA | NA | NA |
aliskiren vs HCTZ | 1 | 1 | 180/173 | 8 | 1.24 [0.97–1.59] | 0.09 | NA | NA | NA |
aliskiren vs atenolol | 1 | 1 | 230/230 | 12 | 0.86 [0.68–1.08] | 0.18 | NA | NA | NA |
BP control rate
The incidence of adverse events
Outcome | No.of SRs | No.of original studies | No.of cases/controls | Follow-up range (weeks) | Estimate (95%CI) | P-value | 95%PI | I2(P*) | Egger’s P value |
---|---|---|---|---|---|---|---|---|---|
Adverse events | |||||||||
aliskiren 75 mg vs placebo | 1 | 5 | 742/740 | 8–13 | 0.96 [0.84–1.08] | 0.48 | [0.78–1.17] | 0% (0.56) | 0.853 |
aliskiren150mg vs placebo | 1 | 10 | 1785/1639 | 8–26 | 0.99 [0.90–1.08] | 0.77 | [0.89–1.10] | 0% (0.65) | 0.43 |
aliskiren300mg vs placebo | 1 | 9 | 1461/1478 | 8–26 | 1.02[0.93–1.12] | 0.68 | [0.91–1.15] | 0% (0.47) | 0.876 |
aliskiren600mg vs placebo | 1 | 3 | 499/494 | 8 | 1.24 [1.07–1.43] | 0.004 | [0.49–3.13] | 0% (0.88) | 0.083 |
aliskiren vs ARBs | 1 | NR | NR | 4–8 | 0.98 [0.89–1.08] | 0.68 | NR | NR | NR |
aliskiren vs lorsartan | 1 | NR | NR | 4–8 | 1.03 [0.79–1.35] | 0.83 | NR | NR | NR |
aliskiren vs valsartan | 1 | NR | NR | 8 | 0.92[0.81–1.05] | 0.2 | NR | NR | NR |
aliskiren vs irbesartan | 1 | NR | NR | 7–8 | 1[0.81–1.23] | 0.99 | NR | NR | NR |
aliskiren vs ACEIs | 1 | 2 | 514/508 | 8–26 | 1[0.89–1.11] | 0.93 | NA | 0% | NA |
aliskiren vs Amlodipine | 1 | 2 | 513/492 | 8–32 | 0.99 [0.81–1.11] | 0.92 | NA | 37% | NA |
aliskiren vs HCTZ | 1 | 1 | 183/176 | 8 | 0.95 [0.74–1.22] | 0.68 | NA | NA | NA |
aliskiren vs atenolol | 1 | 1 | 231/231 | 12 | 0.88 [0.72–1.08] | 0.23 | NA | NA | NA |
Serious adverse events | |||||||||
aliskiren vs placebo | 1 | 8 | 3633/1683 | 8–26 | 0.75 [0.27–2.05] | 0.57 | [0.07–7.71] | 32%(0.17) | 0.811 |
aliskiren vs ARBS | 1 | NR | NR | 4–8 | 0.72 [0.36–1.46] | 0.36 | NR | NR | NR |
aliskiren vs lorsartan | 1 | NR | NR | 4–8 | 0.33 [0.01–8.18] | 0.5 | NR | NR | NR |
aliskiren vs valsartan | 1 | NR | NR | 8 | 0.63 [0.09–4.43] | 0.65 | NR | NR | NR |
aliskiren vs irbesartan | 1 | NR | NR | 7–8 | 0.55[0.18–1.67] | 0.29 | NR | NR | NR |
Withdrawal due to adverse events | |||||||||
aliskiren 75 mg vs placebo | 1 | 5 | 821/817 | 8–13 | 0.69 [0.37–1.29] | 0.24 | [0.25–1.90] | 0%(0.52) | 0.008 |
aliskiren150mg vs placebo | 1 | 7 | 1161/1154 | 8–26 | 0.37[0.16–0.84] | 0.02 | [0.05–2.75] | 38%(0.14) | 0.065 |
aliskiren300mg vs placebo | 1 | 6 | 984/1001 | 8–26 | 0.60 [0.34–1.06] | 0.08 | [0.21–1.74] | 12%(0.34) | 0.365 |
aliskiren600mg vs placebo | 1 | 1 | 166/165 | 8 | 0.14 [0.03–0.62] | 0.009 | NA | NA | NA |
aliskiren vs ARBs | 1 | NR | NR | 4–8 | 0.82 [0.54–1.25] | 0.35 | NR | NR | NR |
aliskiren vs lorsartan | 1 | NR | NR | 4–8 | 0.76[0.28–2.08] | 0.6 | NR | NR | NR |
aliskiren vs valsartan | 1 | NR | NR | 8 | 0.89 [0.50–1.58] | 0.69 | NR | NR | NR |
aliskiren vs irbesartan | 1 | NR | NR | 7–8 | 0.73[0.33–1.61] | 0.43 | NR | NR | NR |
aliskiren vs ACEIs | 2 | 3 | 1145/952 | 8–36 | 0.76 [0.45–1.28] | 0.3 | [0.00–149.77] | 50%(0.13) | 0.953 |
aliskiren vs Amlodipine | 1 | 2 | 513/492 | 8–32 | 0.42 [0.08–2.30] | 0.32 | NA | 65% | NA |
aliskiren vs HCTZ | 1 | 1 | 183/176 | 8 | 1.92 [0.59–6.27] | 0.28 | NA | NA | NA |
aliskiren vs atenolol | 1 | 1 | 231/231 | 12 | 0.6 [0.22–1.62] | 0.31 | NA | NA | NA |
Outcome | No. of SRs | No. of original studies | No. of cases/controls | Follow-up range (weeks) | Estimate (95%CI) | P-value |
---|---|---|---|---|---|---|
Paradoxical blood pressure rise: ΔmsDBP> 5 mmHg | ||||||
aliskiren vs placebo | 1 | 4 | 2110/902 | 8 | 0.27 [0.20–0.37] | < 0.00001 |
aliskiren vs ARBs | 1 | 4 | 2110/701 | 4–9 | 0.86 [0.55–1.36] | 0.53 |
aliskiren vs ramipril | 1 | 2 | 2110/617 | 9–26 | 1.19 [0.69–2.04] | 0.53 |
aliskiren vs HCT | 1 | 1 | 2110/547 | 52 | 1.20 [0.68–2.13] | 0.52 |
ΔmsDBP> 10 mmHg | ||||||
aliskiren vs placebo | 1 | 4 | 2110/902 | 8 | 0.27 [0.15–0.48] | < 0.00001 |
aliskiren vs ARBs | 1 | 4 | 2110/701 | 4–9 | 0.57 [0.27–1.20] | 0.14 |
aliskiren vs ramipril | 1 | 2 | 2110/617 | 9–26 | 0.93 [0.37–2.31] | 0.87 |
aliskiren vs HCT | 1 | 1 | 2110/547 | 52 | 0.70 [0.30–1.67] | 0.42 |
ΔmsSBP> 10 mmHg | ||||||
aliskiren vs placebo | 1 | 4 | 2110/902 | 8 | 0.31 [0.24–0.41] | < 0.00001 |
aliskiren vs ARBs | 1 | 4 | 2110/701 | 4–9 | 0.97 [0.64–1.48] | 0.9 |
aliskiren vs ramipril | 1 | 2 | 2110/617 | 9–26 | 0.69 [0.47–1.01] | 0.05 |
aliskiren vs HCT | 1 | 1 | 2110/547 | 52 | 0.89 [0.57–1.38] | 0.59 |
ΔmsSBP> 20 mmHg | ||||||
aliskiren vs placebo | 1 | 4 | 2110/902 | 8 | 0.40 [0.24–0.67] | 0.0005 |
aliskiren vs ARBs | 1 | 4 | 2110/701 | 4–9 | 1.50 [0.62–3.61] | 0.37 |
aliskiren vs ramipril | 1 | 2 | 2110/617 | 9–26 | 0.66 [0.34–1.29] | 0.22 |
aliskiren vs HCT | 1 | 1 | 2110/547 | 52 | 0.87 [0.40–1.92] | 0.74 |
Cardiovascular outcomes
Outcome | No. of SRs | No. of original studies | No. of cases/controls | Follow-up range (weeks) | Type of metric | Estimate (95%CI) | P-value | 95%PI | I2(P*) | Egger’s P value |
---|---|---|---|---|---|---|---|---|---|---|
aliskiren vs placebo | ||||||||||
NT-proBNP levels | 1 | 3 | 975/956 | 12–48 | SMD | −0.12 [−0.21,-0.03] | 0.01 | [−0.70,0.46] | 0% (0.57) | 0.814 |
BNP levels | 1 | 2 | 151/143 | 6–12 | SMD | −0.08 [−0.31,0.15] | 0.49 | NA | 0%(0.76) | NA |
Plasma renin activity | 1 | 3 | 176/157 | 12–48 | SMD | −0.66 [−0.89,-0.44] | < 0.0001 | [−2.11,0.77] | 0%(0.85) | 0.648 |
Plasma renin concentration | 1 | 2 | 167/149 | 6–26 | SMD | 0.52 [0.30,0.75] | < 0.0001 | NA | 0%(0.72) | NA |
Aldosterone level | 1 | 2 | 151/143 | 6–12 | SMD | −0.09 [−0.32,0.14] | 0.44 | NA | 0%(0.55) | NA |
Mortality | 2 | 3 | 1255/1250 | ≥12 | RR | 0.76 [0.32–1.80] | 0.53 | [0.00,3273.53] | 24%(0.27) | 0.498 |
Myocardial infarction | 1 | 1 | 305/308 | 104 | RR | 0.13[0.02–1.00] | 0.05 | NA | NA | NA |
Stroke | 1 | 1 | 305/308 | 104 | RR | 0.25 [0.03–2.25] | 0.22 | NA | NA | NA |
aliskiren vs enalapril | ||||||||||
Combined cardiovascular mortality and hospitalisation | 1 | 1 | 2340/2336 | 36 | RR | 0.98 [0.90–1.06] | 0.57 | NA | NA | NA |
Renal effects
Outcomes | No. of SRs | No. of original studies | No. of cases/controls | Follow-up range (weeks) | Estimate (95%CI) | P-value |
---|---|---|---|---|---|---|
changes of sCr or eGFR | ||||||
aliskiren vs placebo | 1 | 3 | 6812/5448 | NA | 0.97 [0.81–1.16] | 0.73 |
BUN > 40 mg / dL | ||||||
aliskiren vs placebo | 1 | NA | 1508/753 | 8 | 1.50 [0.06–36.75] | 0.8 |
aliskiren vs ARBs | 1 | NA | 4579/1223 | 8–52 | 1.16 [0.33–4.06] | 0.82 |
aliskiren vs HCT | 1 | NA | 4579/1113 | 8–52 | 0.79 [0.26–2.42] | 0.68 |
Creatinine level > 2.0 mg /dL | ||||||
aliskiren vs placebo | 1 | NA | 1508/753 | 8 | 1.50 [0.06–36.75] | 0.8 |
aliskiren vs ARBs | 1 | NA | 4579/1223 | 8–52 | 0.71 [0.19–2.68] | 0.62 |
aliskiren vs HCT | 1 | NA | 4579/1113 | 8–52 | 4.13 [0.24–71.59] | 0.33 |
eGFR < 30 mL /min /1.73 m2 | ||||||
aliskiren vs ARBs | 1 | NA | 4579/1223 | 8–52 | 0.53 [0.13–2.13] | 0.37 |
aliskiren vs HCT | 1 | NA | 4579/1113 | 8–52 | 3.16 [0.18–56.09] | 0.43 |
Hyperkalaemia | ||||||
aliskiren vs placebo | 1 | NA | 1405/752 | 8 | 1.40 [0.51–3.87] | 0.52 |
aliskiren vs ARBs | 1 | NA | NA | 4–8 | 0.93 [0.51–1.70] | 0.82 |
aliskiren vs HCT | 1 | NA | 5450/1113 | NA | 0.87 [0.62–1.24] | 0.43 |
Author | Indication | Total Sample Size | Follow up | Drug Comparison | Primary Outcome - Results |
---|---|---|---|---|---|
Evangelos C. Rizos, Aris P. Agouridis and Moses S.Elisaf | non-diabetic chronic kidney disease | 14 | 42 | placebo vs. aliskiren 300 mg vs. perindopril 10 mg | UPER: −36% for aliskiren and − 25% for perindopril 10 mg Both treatments vs. placebo: p < 0.05 |
IgA nephropathy | 22 | 36 | placebo vs. aliskiren 300 mg | Reduction in UPCR (g/g) | |
T2DM and hypertension and albuminuria | 26 (crossover design) | 4 × 2-months | Placebo vs. aliskiren300mg vs. irbesartan 300 mg | UAER: −48% for aliskiren and − 51% for irbesartan Both treatments vs. placebo: p < 0.001 | |
T2DM and hypertension and albuminuria | 26 (crossover design) | 4 × 2-months | 150 or 300 or 600 mg aliskiren vs. placebo | UAER: −52% for 600 mg, − 48% for 300 mg, − 36% for 150 mg (600 mg vs. 150 mg: p < 0.05, 600 mg vs. 300 mg: p = NS) All treatments vs. placebo: p < 0.001 |
Prediction intervals and heterogeneity between studies
Publication bias of included studies
AMSTAR 2 classification of included studies
Study | Year | Item1 | Item2 | Item3 | Item4 | Item5 | Item6 | Item7 | Item8 | Item9 | Item10 | Item11 | Item12 | Item13 | Item14 | Item15 | Item16 | Grade |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Yongfei Chen [14] | 2013 | Y | P | N | Y | N | Y | Y | Y | Y | N | Y | Y | Y | Y | N | N | low |
Musini VM [8] | 2017 | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | high |
Gao D [15] | 2011 | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | high |
Zhenfeng Zheng [16] | 2011 | Y | Y | N | Y | N | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | moderate |
Verdecchia P [17] | 2010 | Y | P | N | Y | N | Y | Y | Y | N | Y | Y | N | N | N | N | Y | critically low |
Powers B [18] | 2011 | Y | P | N | Y | N | N | Y | N | Y | Y | Y | Y | Y | Y | N | Y | low |
Stanton AV [19] | 2010 | Y | P | N | N | N | N | P | P | N | Y | Y | N | N | N | N | Y | critically low |
Luo Y [20] | 2018 | Y | Y | Y | Y | N | N | Y | Y | Y | Y | Y | Y | Y | Y | N | Y | low |
Zhang JT [21] | 2015 | Y | Y | Y | Y | Y | Y | Y | Y | Y | N | Y | Y | Y | Y | Y | Y | high |
Zheng SL [22] | 2017 | Y | Y | N | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | N | Y | low |
Gradman AH [23] | 2010 | Y | Y | N | N | N | N | N | Y | N | Y | Y | N | N | Y | N | N | critically low |
White WB [24] | 2011 | Y | P | N | Y | N | N | N | N | N | Y | Y | N | N | Y | N | Y | critically low |
Rizos EC [25] | 2012 | Y | P | N | N | N | Y | Y | P | N | Y | Y | Y | N | Y | N | Y | critically low |
Louvis N [26] | 2018 | Y | P | N | N | N | Y | N | Y | Y | Y | Y | N | N | Y | N | Y | critically low |