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Cochrane Database of Systematic Reviews

Eficacia hipotensora de los inhibidores de la renina para la hipertensión primaria

Información

DOI:
https://doi.org/10.1002/14651858.CD007066.pub3Copiar DOI
Base de datos:
  1. Cochrane Database of Systematic Reviews
Versión publicada:
  1. 05 abril 2017see what's new
Tipo:
  1. Intervention
Etapa:
  1. Review
Grupo Editorial Cochrane:

  1. Grupo Cochrane de Hipertensión

Copyright:
  1. Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

  • Vijaya M Musini

    Correspondencia a: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada

    [email protected]

  • Kendra AK Lawrence

    University of British Columbia, Vancouver, Canada

  • Patricia M Fortin

    Systematic Review Initiative, NHS Blood and Transplant, Oxford, UK

  • Ken Bassett

    Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada

  • James M Wright

    Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada

Contributions of authors

James Wright and Vijaya Musini formulated the idea for the review and developed the basis for the protocol.

Vijaya Musini and Patricia Fortin took the lead roles in searching, identifying, and assessing studies, in data abstraction and analyses, and in writing the review for the original version of this review in 2009 and for the 2011 update.

Vijaya Musini attended to 2017 update by performing a screen to updated search findings, data extraction from clinical study reports, analysis, carrying out a 'Risk of bias' assessment and preparing a 'Summary of findings' table, and editing/writing the review.

Kendra Lawrence attended to the 2017 update of this review by performing a screen to updated search findings, requesting and obtaining CSRs from EMA, data extraction from clinical study reports, analysis, carrying out a 'Risk of bias' assessment, and editing/writing the review.

Patricia Fortin contributed to screening, data extraction from published journal articles, and editing of the review for the 2017 update.

James Wright and Ken Bassett aided in confirming accuracy of data, settling discrepancies in inclusion criteria or data abstraction, and in editing the final version of the review.

Sources of support

Internal sources

  • Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Canada.

External sources

  • Canadian Institues of Health Research, Canada.

Declarations of interest

None known.

Acknowledgements

The authors would like to acknowledge the contribution of Doug Salzwedel, the information specialist of the Hypertension Review Group in updating the search strategy and providing search findings from various databases; Stephen Adams in retrieving innumerable articles; Aaushi Rawat in helping with screening the search results; for identifying studies that meet the inclusion criteria; and doing data abstraction for the two additional studies identified in 2011. We would also like to thank Ciprian Jauca who assisted in editing this review.

Version history

Published

Title

Stage

Authors

Version

2017 Apr 05

Blood pressure lowering efficacy of renin inhibitors for primary hypertension

Review

Vijaya M Musini, Kendra AK Lawrence, Patricia M Fortin, Ken Bassett, James M Wright

https://doi.org/10.1002/14651858.CD007066.pub3

2008 Oct 08

Blood pressure lowering efficacy of renin inhibitors for primary hypertension

Review

Vijaya M Musini, Patricia M Fortin, Ken Bassett, James M Wright

https://doi.org/10.1002/14651858.CD007066.pub2

2008 Apr 23

Blood pressure lowering efficacy of renin inhibitors for primary hypertension

Protocol

Vijaya M Musini, Patricia M Fortin, Ken Bassett, J M and Wright, James M Wright

https://doi.org/10.1002/14651858.CD007066

Differences between protocol and review

The previous version of this review included information from only published journal articles of included studies. However, in the 2017 update we were able to obtain nine clinical study reports (CSRs) of included studies and therefore it was possible to report change in mean sitting systolic blood pressure (MSSBP) and mean sitting diastolic blood pressure (MSDBP) with standard deviation of change from 11 studies, and required to impute missing standard deviation data from only one included study. In all cases where there was a difference between the CSR and published report, data from the CSR was used. Therefore, magnitude of blood pressure reduction and standard deviation of change data may vary from previous versions of the review.

This update includes additional information regarding mortality, non‐fatal serious adverse events, total adverse events and any other common specific adverse events (headache, nasopharyngitis, and diarrhoea). We had already included cough and angioedema as secondary outcomes in the published protocol.

We were also able to reassess the risk of bias of each individual study as detailed information was available in the CSR obtained from EMA and therefore judgement may vary from the previous version of this review. The quality of evidence has been downgraded from high quality in the 2011 update to moderate quality for BP data and to low quality for adverse event data in this 2017 update.

We also graded overall evidence using GRADEpro software and included a 'Summary of findings' table.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Humans; Middle Aged;

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

PRISMA Study flow diagram.
Figuras y tablas -
Figure 1

PRISMA Study flow diagram.

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Methodological quality summary: review authors' judgments about each methodological quality item for each included study.
Figuras y tablas -
Figure 2

Methodological quality summary: review authors' judgments about each methodological quality item for each included study.

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Forest plot of comparison: 1 Aliskiren vs. placebo, outcome: 1.1 Systolic BP.Highly significant subgroup differences were observed therefore mean overall effect size across all doses is not shown. The number of placebo group patients are divided equally in dose ranging studies when more than one dose of aliskiren was used.CSPP100A2308 study the SBP reduction in the treatment and placebo group are reported from the CSR page 61.CSPP100A2405 study the SD for all treatment groups are calculated from SEM reported on page 7 in the CSR .
Figuras y tablas -
Figure 3

Forest plot of comparison: 1 Aliskiren vs. placebo, outcome: 1.1 Systolic BP.

Highly significant subgroup differences were observed therefore mean overall effect size across all doses is not shown. The number of placebo group patients are divided equally in dose ranging studies when more than one dose of aliskiren was used.

CSPP100A2308 study the SBP reduction in the treatment and placebo group are reported from the CSR page 61.

CSPP100A2405 study the SD for all treatment groups are calculated from SEM reported on page 7 in the CSR .

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Forest plot of comparison: 1 Aliskiren vs. placebo, outcome: 1.2 Diastolic BP.Highly significant subgroup differences were observed, therefore mean overall effect size across all doses is not shown. The number of placebo group patients are divided equally in dose ranging studys when more than one dose of aliskiren was used.CSPP100A2308 study the DBP reduction in the treatment and placebo group are reported from the CSR which differ from those reported in the published article. The previous version of this review used data from the published article.CSPP100A2405 study the SD for all treatment groups are calculated from SEM reported from the CSR on page 8.
Figuras y tablas -
Figure 4

Forest plot of comparison: 1 Aliskiren vs. placebo, outcome: 1.2 Diastolic BP.

Highly significant subgroup differences were observed, therefore mean overall effect size across all doses is not shown. The number of placebo group patients are divided equally in dose ranging studys when more than one dose of aliskiren was used.

CSPP100A2308 study the DBP reduction in the treatment and placebo group are reported from the CSR which differ from those reported in the published article. The previous version of this review used data from the published article.

CSPP100A2405 study the SD for all treatment groups are calculated from SEM reported from the CSR on page 8.

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Comparison 1 Aliskiren vs. placebo, Outcome 1 Systolic BP.
Figuras y tablas -
Analysis 1.1

Comparison 1 Aliskiren vs. placebo, Outcome 1 Systolic BP.

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Comparison 1 Aliskiren vs. placebo, Outcome 2 Diastolic BP.
Figuras y tablas -
Analysis 1.2

Comparison 1 Aliskiren vs. placebo, Outcome 2 Diastolic BP.

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Comparison 1 Aliskiren vs. placebo, Outcome 3 Withdrawals due to adverse event.
Figuras y tablas -
Analysis 1.3

Comparison 1 Aliskiren vs. placebo, Outcome 3 Withdrawals due to adverse event.

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Comparison 1 Aliskiren vs. placebo, Outcome 4 Cough.
Figuras y tablas -
Analysis 1.4

Comparison 1 Aliskiren vs. placebo, Outcome 4 Cough.

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Comparison 1 Aliskiren vs. placebo, Outcome 5 Diarrhoea.
Figuras y tablas -
Analysis 1.5

Comparison 1 Aliskiren vs. placebo, Outcome 5 Diarrhoea.

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Comparison 2 Aliskiren150 mg vs. Aliskiren 75 mg, Outcome 1 Systolic BP.
Figuras y tablas -
Analysis 2.1

Comparison 2 Aliskiren150 mg vs. Aliskiren 75 mg, Outcome 1 Systolic BP.

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Comparison 2 Aliskiren150 mg vs. Aliskiren 75 mg, Outcome 2 Diastolic BP.
Figuras y tablas -
Analysis 2.2

Comparison 2 Aliskiren150 mg vs. Aliskiren 75 mg, Outcome 2 Diastolic BP.

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Comparison 3 Aliskiren 300 mg Vs. Aliskiren 75 mg, Outcome 1 SBP.
Figuras y tablas -
Analysis 3.1

Comparison 3 Aliskiren 300 mg Vs. Aliskiren 75 mg, Outcome 1 SBP.

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Comparison 3 Aliskiren 300 mg Vs. Aliskiren 75 mg, Outcome 2 DBP.
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Analysis 3.2

Comparison 3 Aliskiren 300 mg Vs. Aliskiren 75 mg, Outcome 2 DBP.

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Comparison 4 Aliskiren 300 mg vs. Aliskiren 150 mg, Outcome 1 Systolic BP.
Figuras y tablas -
Analysis 4.1

Comparison 4 Aliskiren 300 mg vs. Aliskiren 150 mg, Outcome 1 Systolic BP.

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Comparison 4 Aliskiren 300 mg vs. Aliskiren 150 mg, Outcome 2 Diastolic BP.
Figuras y tablas -
Analysis 4.2

Comparison 4 Aliskiren 300 mg vs. Aliskiren 150 mg, Outcome 2 Diastolic BP.

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Comparison 5 Aliskiren 600 mg vs. Aliskiren 150 mg, Outcome 1 SBP.
Figuras y tablas -
Analysis 5.1

Comparison 5 Aliskiren 600 mg vs. Aliskiren 150 mg, Outcome 1 SBP.

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Comparison 5 Aliskiren 600 mg vs. Aliskiren 150 mg, Outcome 2 DBP.
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Analysis 5.2

Comparison 5 Aliskiren 600 mg vs. Aliskiren 150 mg, Outcome 2 DBP.

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Comparison 6 Aliskiren 600 mg vs. Aliskiren 300 mg, Outcome 1 Systolic BP.
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Analysis 6.1

Comparison 6 Aliskiren 600 mg vs. Aliskiren 300 mg, Outcome 1 Systolic BP.

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Comparison 6 Aliskiren 600 mg vs. Aliskiren 300 mg, Outcome 2 Diastolic BP.
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Analysis 6.2

Comparison 6 Aliskiren 600 mg vs. Aliskiren 300 mg, Outcome 2 Diastolic BP.

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Aliskiren compared to placebo for primary hypertension

Patient or population: primary hypertension

Setting: Outpatient

Intervention: Aliskiren

Comparison: Placebo

Outcomes

Anticipated absolute effects* (95% CI)mmHg

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Effect with placebo1

Effect with Aliskiren2

Systolic BP ‐ Aliskiren 75 mg vs. placebo

2.9 lower to 10.0 lower

2.97 lower (4.76 lower to 1.18 lower)

‐

1100
(5 RCTs)

⊕⊕⊕⊝
MODERATE 3

Systolic BP ‐ Aliskiren 150 mg vs. placebo

2.0 lower to 10.0 lower

5.95 lower (6.85 lower to 5.06 lower)

‐

3786
(12 RCTs)

⊕⊕⊕⊝
MODERATE 4

Systolic BP ‐ Aliskiren 300 mg vs. placebo

2.9 lower to 10.0 lower

7.88 lower (8.94 lower to 6.82 lower)

‐

3009
(10 RCTs)

⊕⊕⊕⊝
MODERATE 5

Systolic BP ‐ Aliskiren 600 mg vs. placebo

3.8 lower to 5.3 lower

11.35 lower (14.43 lower to 8.27 lower)

‐

393
(2 RCTs)

⊕⊕⊝⊝
LOW 6,7

Diastolic BP ‐ Aliskiren 75 mg vs placebo

3.2 lower to 8.6 lower

2.05 lower (3.13 lower to 0.96 lower)

‐

1100
(5 RCTs)

⊕⊕⊕⊝
MODERATE 3

Diastolic BP ‐ Aliskiren 150 mg vs placebo

3.0 lower to 8.6 lower

3.16 lower (3.74 lower to 2.58 lower)

‐

3783
(12 RCTs)

⊕⊕⊕⊝
MODERATE 4

Diastolic BP ‐ Aliskiren 300 mg vs placebo

3.2 lower to 8.6 lower

4.49 lower (5.17 lower to 3.82 lower)

‐

3001
(10 RCTs)

⊕⊕⊕⊝
MODERATE 5

Diastolic BP ‐ Aliskiren 600 mg vs placebo

6.2 lower to 6.3 lower

5.86 lower (7.73 lower to 3.99 lower)

‐

393
(2 RCTs)

⊕⊕⊝⊝
LOW 6,7

Diarrhoea ‐

Aliskiren 600 mg vs placebo

14 per 1,000

95 per 1,000
(34 to 266)

RR 7.00
(2.48 to 19.72)

592
(2 RCTs)

⊕⊕⊝⊝
LOW 6,7

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio; MD: Mean Difference

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1. Range of mean decrease in SBP and DBP mmHg as compared to baseline in the individual trials in the placebo group.

2. Effects in Aliskiren group represent the blood pressure lowering effect in excess of that with placebo.

3. Downgraded by 1 level for serious risk of bias (due to high likelihood of attrition, selective reporting and funding bias in all 5 included studies). Also study CSPP100A2204 had high likelihood of selection bias.

4. Downgraded by one level for serious risk of bias (due to high likelihood of attrition, selective reporting and funding bias in all 12 included studies).

5. Downgraded by one level for serious risk of bias (due to high likelihood of attrition, selective reporting and funding bias in all 10 included studies).

6. Downgraded by 1 level for serious risk of bias (due to high likelihood of attrition, selective reporting and funding bias in both included studies).

7. Downgraded by 1 more level due to wide confidence interval.
Figuras y tablas -
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Table 1. Reported as table 21 in the FDA medical review (page 51): Reviewers mean placebo‐corrected change from baseline in BP by dose and gender based on 5 placebo controlled studies

Dose

Female

Male

SBP mmHg

DBP mmHg

SBP mmHg

DBP mmHg

75 mg

‐1.3

‐1.1

‐3.6

‐2.9

150 mg

‐5.5

‐2.9

‐5.9

‐3.5

300 mg

‐9.4

‐4.8

‐9.0

‐5.4

600 mg

‐12.6

‐6.4

‐10.7

‐6.5

75 mg

‐1.3

‐1.1

‐3.6

‐2.9
Figuras y tablas -
Table 1. Reported as table 21 in the FDA medical review (page 51): Reviewers mean placebo‐corrected change from baseline in BP by dose and gender based on 5 placebo controlled studies
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Table 2. Reported as table 22 in the FDA medical review (page 51): Reviewers mean placebo‐corrected change from baseline in BP by dose and age based on 5 placebo controlled studies

Dose

Age < 65 years

Age > 65 years

SBP mmHg

DBP mmHg

SBP mmHg

DBP mmHg

75 mg

‐2.7

‐1.9

‐3.6

‐3.4

150 mg

‐5.5

‐2.9

‐6.9

‐4.8

300 mg

‐9.7

‐5.2

‐7.1

‐4.4

600 mg

‐11.5

‐6.6

‐11.6

‐6.4

75 mg

‐2.7

‐1.9

‐3.6

‐3.4
Figuras y tablas -
Table 2. Reported as table 22 in the FDA medical review (page 51): Reviewers mean placebo‐corrected change from baseline in BP by dose and age based on 5 placebo controlled studies
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Table 3. Reported as table 23 in the FDA medical review (page 52): Reviewers mean placebo‐corrected change from baseline in BP by dose and race based on 5 placebo controlled studies

Dose

White

Black

Asian

SBP mmHg

DBP mmHg

SBP mmHg

DBP mmHg

SBP mmHg

DBP mmHg

75 mg

‐2.1

‐1.7

‐2.8

0.2

‐8.8

‐3.2

150 mg

‐6.5

‐3.5

‐5.5

‐1.4

‐3.7

‐2.9

300 mg

‐9.6

‐4.8

‐6.1

‐2.6

‐12.7

‐6.3

600 mg

‐12.3

‐6.7

‐8.7

‐3.5

‐11.2

‐9.4
Figuras y tablas -
Table 3. Reported as table 23 in the FDA medical review (page 52): Reviewers mean placebo‐corrected change from baseline in BP by dose and race based on 5 placebo controlled studies
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Table 4. Comparing MSSBP and MSDBP effect size of previous review versus present update after obtaining information from Clinical study Reports

Dose of Aliskiren mg/day

Previous version without access to information from CSR

Present version with access to information from CSR

MSSBP mmHg

MD with 95% CI

MSDBP mmHg

MD with 95% CI

MSSBP mmHg

MD with 95% CI

MSDBP mmHg

MD with 95% CI

Aliskiren 75 mg vs. Placebo

‐2.64 (‐4.06 to ‐1.23)

‐2.07 (‐2.94 to ‐1.20)

‐2.97 (‐4.76 to ‐1.18)

‐2.05 (‐3.13 to ‐0.96)

Aliskiren 150 mg vs. Placebo

‐5.55 (‐6.39 to ‐4.71)

‐2.91 (‐3.46 to ‐2.37)

‐5.95 (‐6.85 to ‐5.06)

‐3.16 (‐3.74 to ‐2.58)

Aliskiren 300 mg vs. Placebo

‐7.93 (‐8.77 to ‐7.08)

‐4.76 (‐5.33 to ‐4.19)

‐7.88 (‐8.94 to ‐6.82)

‐4.49 (‐5.17 to ‐3.82)

Aliskiren 600 mg vs. Placebo

‐11.36 (‐13.53 to ‐9.19)

‐6.57 (‐7.92 to ‐5.23)

‐11.35 (‐14.43 to ‐8.27)

‐5.86 (‐7.73 to ‐3.99)

MSSBP: mean sitting systolic blood pressure; MSDBP: mean sitting diastolic blood pressure;

Figuras y tablas -
Table 4. Comparing MSSBP and MSDBP effect size of previous review versus present update after obtaining information from Clinical study Reports
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Table 5. Study identifier(s) in various websites of individual studies meeting the inclusion criteria

Novartis Clinical Trial Results Database identifier

used for study identification

in this review

Journal‐Published

Author /year

Registered on

Novartis Clinical Trial

Results Database

Registered on

ClinicalTrials.gov

CSR* received from EMA

Request to

EMA was made on

November 15th 2015.

Weeks waited

to obtain CSR

CSPA100A1301

No journal publication

Results NOT posted

NCT01237223

Results posted

EMA does NOT possess

‐

CSPA100A2305

Littlejohn 2013

Results posted

NCT00739973

Results posted

EMA does NOT possess

‐

CSPP100A1201

Kushiro 2006

Results NOT posted

NOT registered

Mar 11, 2016

16

CSPP100A1301

No journal publication

Results posted

NCT00344110

Results NOT posted

May 23, 2016

27

CSPP100A2201

Gradman 2005

Results NOT posted

NOT registered

Jan 25, 2016

10

CSPP100A2203

Pool 2007

NOT FOUND

NOT registered

Apr 12, 2016

21

CSPP100A2204

Villamil 2007

Results NOT posted

NCT00219024

Results posted

Apr 6, 2016

20

CSPP100A2308

Oh 2007

Results NOT posted

NCT00219128

Results NOT posted

Feb 20, 2016

14

CSPP100A2323

Schmieder 2009

Results posted

NCT00219154

Results NOT posted

May 27, 2016

27

CSPP100A2327

Oparil 2007

Results NOT posted

NOT registered

June 16, 2016

30

CSPP100A2328

Puig 2009

Results posted

NOT registered

EMA does NOT possess

‐

CSPP100A2405

Villa 2012

Results posted

NCT00706134

Results posted

December 22, 2015

5
Figuras y tablas -
Table 5. Study identifier(s) in various websites of individual studies meeting the inclusion criteria
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Table 6. Comparing MSSBP and MSDBP reduction between aliskiren doses from the same study

Dose comparison

SBP WMD with 95% CI

DBP WMD with 95% CI

Comment

Aliskiren 150 mg vs 75 mg

‐1.89 (‐3.16 to ‐0.62)

‐0.80 (‐1.58 to ‐0.03)

Aliskiren 150 mg reduces SBP and DBP more than

75 mg by 2/1 mmHg

Aliskiren 300 mg vs 75 mg

‐5.10 (‐6.79 to ‐3.40)

‐2.49 (‐3.53 to ‐1.45)

Aliskiren 300 mg reduces SBP and DBP more than

75 mg 5/3 mmHg

Aliskiren 300 mg vs 150 mg

‐2.62 (‐3.38 to ‐1.87)

‐1.80 (‐2.28 to ‐1.32)

Aliskiren 300 mg reduces SBP and DBP more than

150 mg 3/2 mmHg

Aliskiren 600 mg vs 150 mg

‐3.40 (‐5.58 to ‐1.23)

‐2.20 (‐3.55 to ‐0.85)

Aliskiren 600 mg reduces SBP and DBP more than

150 mg by 3/2mmHg

Aliskiren 600 mg vs 300 mg

‐0.61 (‐2.78 to 1.56)

‐0.68 (‐2.03 to 0.67)

No significant difference was observed
Figuras y tablas -
Table 6. Comparing MSSBP and MSDBP reduction between aliskiren doses from the same study
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Table 7. Mortality during single‐blind, double‐blind and withdrawal period in the 12 included studies

Study identifier

Single‐blind period

Double‐blind period

Withdrawal period

CSPA100A1301

No deaths

No deaths

No deaths

CSPA100A2305

No deaths

No deaths

No deaths

CSPP100A1201

One death in placebo group during observation period due to pancreatic carcinoma and metastases to liver.

One death occurred in aliskiren 150 mg monotherapy on day 41 of the study, due to drug intoxication. The overdose was attributed to a psychiatric drug prescribed prior to start of the study, and a diagnosis of manic depressive psychosis was recorded.

No deaths

CSPP100A1301

No deaths

No deaths

No deaths

CSPP100A2201

No deaths

No deaths

No deaths

CSPP100A2203;

No deaths

One death occurred in the placebo arm on day 16 from "natural causes".

One death occurred in the valsartan 160 mg arm (day 26) as a result of motor vehicle accident.

No deaths

CSPP100A2204

No deaths

One death was reported in the Aliskiren/HCTZ 150/25 mg group due to thoracic trauma from a motor vehicle accident.

No deaths

CSPP100A2308

No deaths

No deaths

No deaths

CSPP100A2323

1 death occurred in placebo run‐in phase. Patient hospitalized due to supraventricular tachycardia and abdominal pain and died due to stroke after discontinuing from the study.

No deaths

One death occurred in the aliskiren/HCTZ 150/300 mg group from acute bronchopneumonia and associated sepsis during the 30‐day follow‐up period after discontinuing the study.

CSPP100A2327

No deaths

2 deaths reported.

1 death in aliskiren group on day 41 due to myocardial infarction.

1 death in valsartan group on day 13 and the cause was reported as hypertensive arteriosclerotic cardiovascular disease with SAE of sudden death.

There were no deaths in placebo arm or combination therapy group.

No deaths

CSPP100A2328

No deaths

No deaths

No deaths

CSPP100A2405:

One death occurred during the follow‐up period of the study from pneumonia leading to respiratory failure (day of death not provided). Further information regarding this death is described in the patient narratives of the CSR, which we do not have access to yet. Within the CSR body, the arm of the study that this participant belongs to has been redacted.

In the 2008 FDA Medical Review report, a death due to colon cancer is reported as occurring within CSPP100A2204 (N = 1, aliskiren 300 mg). The medical review states "no other details were provided". For our comments on this please see Discussion.

CSR: clinical study report; HTCZ: hydrochlorothiazide; SAE: serious adverse event

Figuras y tablas -
Table 7. Mortality during single‐blind, double‐blind and withdrawal period in the 12 included studies
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Table 8. Non‐fatal serious adverse events during wash out, single‐blind, double‐blind and withdrawal period

Study identifier

Wash out period

Single blind period

Double blind period

Withdrawal period

CSPA100A1301

Not reported

Not reported

No SAEs were reported in the aliskiren monotherapy group.

2 in amlodipine 2.5 mg; 1 in amlodipine 5 mg; and 1 in aliskiren 150/amlodipine 5 mg combination arm (detail regarding SAE was not reported)

Not reported

CSPA100A2305

Not reported

Not reported

9 SAEs reported.

2 in placebo and 7 in other treatment groups (retinal detachment, abdominal mass, bronchitis, calculus ureteric, gastroenteritis, hand fracture, hydronephrosis, pneumonia, and cerebrovascular accident).

None occurred in aliskiren 150 mg or 300 mg groups.

Not reported

CSPP100A1201

Not reported

Reported 1 SAE in the single‐blind period ‐ infectious enterocolitis/dehydration (N = 1, 55M, placebo).

2 SAEs in the double‐blind period:

cerebral infarction (N = 1, 69F, placebo);

acute myocardial infarction (N = 1, 58F, aliskiren 75 mg).

Not reported

CSPP100A1301

Not reported

Not reported

2 SAEs reported.

1 SAE in placebo due to myocardial infarction.

The other in the losartan 50 mg group due to right medullary infarction.

None in aliskiren 150 mg group.

Not reported

CSPP100A2201

One in washout period ‐ transient Ischaemic attack

Two in the single‐blind run‐in phase ‐ anxiety; and diverticulitis and

2 SAEs in irbesartan group ‐ Intravertebral disc protrusion; and bipolar depression.

Two in the withdrawal period in placebo group ‐ Left ventricular failure; and gout and infective arthritis).

CSPP100A2203;

Not reported

Reported 6 SAE.

1 bile duct cancer, 1 diverticulitis, 1 pregnancy, 1 mild melanorrhagia and gastric pain, 1 myocardial infarction, and 1 squamous cell carcinoma.

8 SAEs reported.

2 in Placebo: 1 due to natural cause and 1 due to myocardial infarction requiring hospitalization on day 46 resulting in study drug discontinuation.

1 in aliskiren 75 mg on day 4 coronary artery disease requiring hospitalization resulting in study discontinuation. Patient required quadruple bypass surgery.

1 in aliskiren 300 mg on day 42 pregnancy resulting in study discontinuation.

1 in valsartan 160 mg on day 28 ‐ angioneurotic oedema resulting in study discontinuation, dyspnoea and chest pressure.

Aliskiren 150 mg/valsartan 160 mg (N = 1, Day 29) motor vehicle accident requiring hospitalization; not discontinued from study.

1 in aliskiren 75 mg/valsartan 80 mg on day 3 post‐study.

CSPP100A2204*

Not reported

4 SAE due to (lung cancer, fractured leg, angina and urinary tract infection)

28 patients experienced at least 1 SAE in the monotherapy and combination therapy treatment groups.

1 in A 75 mg ‐ due to renal colic; 1 in aliskiren 150 mg due to haemorrhagic diarrhoea; none in aliskiren 300 mg; 1 in HCTZ 6.25 mg due to neoplasm of skin; 3 in HCTZ 12.5 mg ‐ due to breast cancer, joint injury and pregnancy; 2 in HCTZ 25 mg due to deep vein thrombosis and lymphadenopathy; 5 in aliskiren 75 mg/HCTZ 12.5 mg due to (diplopia, IIIrd nerve paresis, mood disorder, phlebothrombosis, psychotic disorder, small intestinal obstruction and syncope); 4 in aliskiren 75 mg/HCTZ 25 mg due to (cerebral infarction, dysarthria, physical disability, pregnancy and renal colic); 2 in aliskiren 150 mg/ HCTZ 6.25 mg ulcerative colitis, pregnancy); 3 in aliskiren 150 mg/ HCTZ 12.5 mg (non‐cardiac chest pain, pregnancy, syncope); 2 in aliskiren 150 mg/ HCTZ 25 mg (lung neoplasm, road traffic accident); 2 in aliskiren 300 mg/ HCTZ 12.5 mg (diabetes mellitus, lung disorder); 1 in aliskiren 300 mg/HCTZ 25 mg (coronary artery disease).

There were no SAEs in the placebo group.

Not reported

CSPP100A2308

2 SAEs reported during washout period ‐ 1 due to subarachnoid haemorrhage due to rupture of cerebral aneurysm on day 8;

1 due to partial small bowel obstruction on day 13

One SAE ‐ bladder carcinoma prior to randomization and before receiving double‐blind study drug. Patient was randomized to placebo but later discontinued due to unsatisfactory therapeutic effect;

4 SAEs reported.

1 SAE in aliskiren 150 mg on day 27‐ unstable angina and increased blood pressure;

2 SAEs in aliskiren 300 mg ‐ hospitalization for acute appendicitis on day 34; hospitalization for depression on day 51;

1 SAE in aliskiren 600 mg of hospitalization for pain/bodily injury on day 35.

No SAE reported in the placebo group.

One SAE was reported during withdrawal period in aliskiren 150 mg of serious venous occlusion and thrombosis of the right eye on day 8 withdrawal period).

CSPP100A2323

data at week 3 and week 6 not available

Not reported

Not reported

During 26 weeks double‐blind treatment period

19 SAEs reported. 10 in aliskiren group and 9 in HCTZ group.

Not reported

CSPP100A2327*

not reported

Not reported

20 SAEs reported.

5 in placebo group ‐ atrial flutter, cerebrovascular accident, headache, hypertension, hypertensive crisis and ventricular tachycardia);

8 in aliskiren group ‐ 1 gastritis, 1 grand mal convulsions, 1 intestinal poly, 2 myocardial infarction, 1 non‐cardiac chest pain, 1 peripheral vascular disease, 1 acute renal failure);

6 in valsartan group ‐ 1 angina pectoris, 1 arteriosclerosis, 1 breast cancer, 1 bronchitis, 1 COPD, 1 facial paresis, 1 ovarian cancer, 1 pneumonia, 1 pulmonary oedema);

3 in aliskiren/valsartan group ‐ 1 aortic aneurysm, 1 intravertebral disc protrusion, 1 prostate cancer and 1 thyroidectomy).

The FDA medical review (2007) also reported two cases of renal carcinoma occurred (N = 1, placebo, day 20 post‐study; N = 1, aliskiren, day 44 post‐study). For our comments on this, please see Discussion.

Not reported

CSPP100A2328

11 patients had serious AEs during the washout and placebo run‐in periods (detail of which are not provided).

Not reported

1 SAE was reported in aliskiren 75 mg group ‐ cardiac chest pain;

2 in aliskiren 150 mg group ‐ rectal bleeding due to anal ulcer and episode of secondary anaemia; basal cell carcinoma;

1 in the 300 mg group ‐TIA with concomitant nausea and dyspnoea; and

2 in the placebo group ‐ prostate cancer; accelerated hypertension with left facial numbness.

Not reported

CSPP100A2405:

Reported 2 SAEs in the washout period; Detail not provided in CSR.

Three in the single‐blind placebo run‐in period. Detail not provided in CSR.

6 SAEs were reported.

2 in aliskiren 75 mg group ‐ erysipelas (skin infection) and osteoarthritis;

3 in aliskiren 150 mg group ‐ severe glaucoma; moderate haemorrhoids; and mild hemorrhagic stroke;

none in aliskiren 300 mg group; and

1 in the placebo group ‐ vertigo, wrist fracture, concussion, and head contusion subsequent to a fall.

Not reported

COPD: chronic obstructive pulmonary disease; CSR: clinical study report; HTCZ: hydrochlorothiazide; SAE: serious adverse event; TIA: transient ischaemic attack

Figuras y tablas -
Table 8. Non‐fatal serious adverse events during wash out, single‐blind, double‐blind and withdrawal period
Ir a la tabla de la revisión
Table 9. Total adverse events during double blind treatment period

Study Identifier

Total AEs and Common AEs as reported in the corresponding available CSR

A = Aliskiren; P = Placebo

CSPA100A1301

Total AEs: A150 =15(7.8%); A 300 = 18(8.9%) and P = 22(7.7%)

Headache: A150 =13( 6.7%); A 300 =15(7.4%) and P = 20(10.1%)

Periphaeral edema: A150 = 2(1.0%); A 300 = 3(1.5%) and P = 2(1%)

CSPA100A2305

Total AEs: A150 = 40.1%; A 300 = 46.7%; A 600 = 52.4%; P = 43%

Headache: A150 = 12(7%); A300 = 13(7.7%); A600 = 9(5.4%); P = 16(9.7%)

Nasopharyngitis: A 150 = 5(2.9%); A 300 = 6(3.6%); A 600 = 3(1.8%); P = 10(6.1%)

Dizziness: A 150 = 2(1.2%); A 300 = 9(5.3%); A 600 = 5(3%); P = 7(4.2%)

Diarrhoea:A 150 = 2(1.2%); A 300 = 3(1.8%); A 600 = 19 (11.4%); P = 2(1.2%)

Nausea: A 150 = 2(1.2%); A 300 = 3(1.8%); A 600 = 0%; P = 4(2.4%)

CSPP100A1201

Total AEs: A75 = 61(53%); A150 = 58(51.8%); A 300 = 62(54.9%); P = 58(50.4)%

Headache: A75 = 3(2.6%); A 150 = 3(2.7%); A 300 = 6 (5.3%) and P = 4(3.5%)

Nasopharyngitis:A75 = 24(20.9%); A150 = 20(17.9%); A300 = 20(17.7%); P = 16(13.9%)

Back pain:A75 = 2(1.7%); A150 = 0%; A300 = 0% and P = 0%

Diarrhoea: A75 = 1(0.9%); A150 = 1(0.9%); A300 = 4(3.5%) and P = 1(0.9%)

Vertigo: A75 =0%; A150 = 0%); A300 = 1(0.9%) and P = 2(1.7%)

CSPP100A1301

Total AEs: A150 = 152(50.3%), P = 66(42.3%)

Nasopharyngitis: A150 = 48(15.9%), P = 13(8.3%)

Headache: A150 = 9(3.0%), P = 6(3.8%)

Occult blood positive: A150 = 9 (3.0%), P =5 (3.2%)

CSPP100A2201

Total AEs: A150 = 127 (26.8%); A300 = 130 (36.2%); A600 = 43 (33.1%); P = 32 (32.1%)

Headache: A150 = 3 (2.4%); A300 = 8 (6.2%); A600 = 6 (4.6%); P = 7 (5.3%)

Diarrhoea: A150 = 2 (1.6%); A300 = 1 (0.8%); A600 = 9 (6.9%); P = 2 (1.5%)

Dizziness: A150 = 2 (1.6%); A300 = 4 (3.1%); A600 = 3 (2.3%); P = 5 (3.8%)

Fatigue: A150 = 1 (0.8%); A300 = 5 (3.8%); A600 = 2 (1.5%); P = 4 (3.1%)

CSPP100A2203;

Total AEs: A75 = 63(35.2%); A150 = 59(33.1%); A300 = 50(28.6%) and P = 57(32.2%)

Headache: A75 = 15(8.4%); A150 = 9(5.1%;) A 300 = 7(4.0%) and P = 15(8.5%)

Fatigue: A75 = 7(3.9%); A150 = 4(2.2%;) A 300 = 4(2.3%) and P = 4(2.3%)

Back pain: A75 = 2(1.1%); A150 = 4(202%;) A 300 = 3(1.7%) and P = 2(1.1%)

Diarrhoea: A75 = 2(1.1%); A150 = 1(0.6%;) A 300 = 5(2.9%) and P = 3(1.7%)

Dizziness: A75 = 4(2.2%); A150 = 4(2.2%;) A 300 = 3(1.7%) and P = 2(1.1%)

CSPP100A2204

Total AEs: A75 = 69(37.5%); A150 = 69(37.3%); A300 = 71 (39.2%); P = 85(44%)

Headache: A75 = 13(7.1%); A 150 = 13(7%); A 300 = 10 (5.5%); P = 26 (13.5%)

Nasopharyngitis: A75 = 9( 4.9%); A150 = 5(2.7%;) A300 = 3 (1.7%); P = 10 (5.2%)

Diarrhoea: A75 = 3(1.6%); A150 = 3(1.6%); A300 = 4(2.2%); P = 1(0.5%)

Cough: A75 = 1(0.5%); A150 = 2(1.1%); A300 = 1(0.6%); P = 1(0.5%)

Dizziness: A75 = 1(0.5%); A150 = 1(0.5%); A300 = 3(1.7%); P = 2(1.0%)

Peripheral edema: A75 = 4(2.2%); A150 = 3(1.6%); A300 = 2(1.1%); P = 1(0.5%)

CSPP100A2308

Total AEs: A150 = 40.1%; A 300 = 46.7%; A 600 = 52.4%; P = 43%

Headache: A150 = 12(7%); A300 = 13(7.7%); A600 = 9(5.4%); P = 16(9.7%)

Nasopharyngitis: A 150 = 5(2.9%); A 300 = 6(3.6%); A 600 = 3(1.8%); P = 10(6.1%)

Dizziness: A 150 = 2(1.2%); A 300 = 9(5.3%); A 600 = 5(3%); P = 7(4.2%)

Diarrhoea: A 150 = 2(1.2%); A 300 = 3(1.8%); A 600 = 19 (11.4%); P = 2(1.2%)

Nausea: A 150 =2 (1.2%); A 300 = 3(1.8%); A 600 =0%; P = 4(2.4%)

CSPP100A2323

Total AEs at 6 weeks : A 26.4%; P = 28.5% (numbers not reported)

Other AE were not reported at week 6.

CSPP100A2327

Total AEs: A150 to 300 = 149(34%) and P = 168(37%)

Headache: A150 to 300 = 14(3.2%); P = 41(9%)

Diarrhoea*: A150 to 300 = 2.3%; P = not reported

Nasopharyngitis: A150 to 300 = 16(3.7%) ; P = 9(2%)

Dizziness: A 150 to 300 = 8(1.8%) ; P = 9(2%)

Fatigue:A 150 to 300 = 4(0.9%) ; P = 5(1.1%)

Nausea: A 150 to 300 = 6(1.4%) ; P = 11(2.4%)

CSPP100A2328

Total AEs: A75 = 57(37.3%); A150 = 59(34.7%); A300 = 56(35.4%); P = 60(37.5%)

Headache: A75 = 12(7.8%); A150 = 7(4.1%); A300 = 10(6.3%) and P = 9(5.6%)

Nasopharyngitis: A75 = 2(1.3%); A150 = 2(1.2%); A300 = 5(3.2%) and P = 3(1.9%)

Diarrhoea: A75 = 7(4.6%); A150 = 2(1.2%); A300 = 1(0.6%) and P = 1(0.6%)

Cough: A75 = 1(0.7%); A150 = 4(2.4%); A300 = 1(0.6%) and P = 3(1.9%)

Dizziness: A75 = 1(0.7%); A150 = 5(2.9%); A300 = 1(0.6%) and P = 3(1.9%)

CSPP100A2405:

Total AEs: A75 = 36(18.8%); A150 = 41(21.7%); A300 = 36(19.1%); P = 39(21.0%)

Headache: A75 = 4(2.1%);A150 = 2(1.1%); A300 = 1(1.1%); P = 4(2.1%)

Influenza: A75 = 1(0.5%); A150 = 4(2.1%); A300 = 1(1.1%); P = 1(0.5%)

Figuras y tablas -
Table 9. Total adverse events during double blind treatment period
Ir a la tabla de la revisión
Table 10. Listing reasons for withdrawal due to adverse events

Study Identifier

Reasons for increased withdrawal due to adverse events

CSPA100A1301

Not reported.

CSPA100A2305

Not reported.

CSPP100A1201

Significant adverse events occurred for N = 7 patients, leading to discontinuation from study, as described below.

  • Placebo (N = 3): moderately elevated blood pressure (N = 1); moderate rotary vertigo and moderately elevated blood pressure (N = 1); cerebral infarction (N = 1); aliskiren 75 mg (N = 1): acute myocardial infarction (N = 1).

  • Aliskiren 150 mg (N = 1): moderately elevated blood pressure (N = 1); aliskiren 300m g (N = 2); moderately elevated blood pressure (N = 1; drug eruption (N = 1). Adverse events suspected to be study drug‐related occurred in N = 5 patients. These events improved or resolved upon discontinuation of study drug.

CSPP100A1301

  • Placebo = 7(4.5%): blood pressure increased (N = 3, 1.9%); headache (N =1, 0.6%); SBP increased (N = 1, 0.6%); gastroenteritis (N = 1, 0.6%); myocardial infarction (N = 1, 0.6%). Also, 6 (3.8%) patients withdrew due to abnormal test procedure results.

  • Aliskiren 150 mg = 5 (1.7%); 5 (1.7%): joint pain (N =1, 0.3%); blood pressure increased (N =1, 0.3%); dizziness (N =1, 0.3%); head discomfort (N =1, 0.3%); headache (N = 1, 0.3%); and nausea (N =1, 0.3%). Also 5(1.7%) patients withdrew due to abnormal test procedure results.

CSPP100A2201

A total of N = 18 patients discontinued from the study due to AEs. It was suspected that 2/3 of these discontinuations were for reasons drug‐related. Headaches resulted in the discontinuation for N = 3 patients.

CSPP100A2203;

Most frequent reasons for 12 discontinuations are: fatigue (N = 5, 0.4%), headache (N = 3, 0.3%), diarrhoea (N = 2, 0.2%), and peripheral oedema (N = 2, 0.2%).

Reasons for 14 discontinuations from AE (safety population).

  • Placebo (N = 6, 3.4): myocardial infarction (N = 1, 0.6%); tachycardia (N = 1, 0.6%); diarrhoea (N = 1, 0.6%); fatigue (N = 1; 0.6%), peripheral oedema (N = 1, 0.6%); sudden death (N = 1, 0.6%); headache (N = 1, 0.6%).

  • Aliskiren 75 mg (N = 5): coronary artery disease (N = 1, 0.6%); abdominal pain (N = 1, 0.6%); diarrhoea (N = 1, 0.6%); oedema (N = 1, 0.6%); headache (N = 1, 0.6%); syncope (N = 1, 0.6%); dermatitis bullous (N = 1, 0.6%); eczema (N = 1, 0.6%).

  • Aliskiren 150 mg (N = 3, 1.7%): fatigue (N = 1, 0.6%); blood creatine phosphokinase increased (N = 1, 0.6%); pulse pressure increased (N = 1, 0.6%); migraine (N = 1, 0.6%); cold sweat (N = 1, 0.6%).

The FDA medical review reports facial oedema (N = 1, 0.6%) that appears to be angioedema, resulting in discontinuation from study; however, this is not reported in CSR 2203.

  • Aliskiren 300 mg (N = 3, 1.7%): vertigo (N = 1, 0.6%); influenza‐like illness (N = 1, 0.6%); flank pain (N = 1, 0.6%); pregnancy (N = 1, 0.6%).

  • Additionally, in the aliskiren 150 mg arm, discontinuation from study occurred for (N = 1, 0.6%) abnormal laboratory values.

CSPP100A2204

The range of AEs resulting in study discontinuation is 0% is the aliskiren 150 mg arm of the study to 4.4% in the aliskiren 300 mg arm (N = 7). The most frequent AE resulting in study discontinuation is headache (N = 12, 0.4%).

Reasons for discontinuations from adverse events ‐ N = 62 (2.2%).

  • Placebo (N = 7, 3.6%): blood pressure increased (N = 1, 0.5%; depression (N = 1, 0.5%); dizziness (N = 1, 0.5%); eye pruritis (N = 1, 0.5%); gastritis (N = 1, 0.5%); insomnia (N = 1, 0.5%): lacrimation increased (N = 1, 0.5%); tinnitus (N = 1, 0.5%).

  • Aliskiren 75 mg (N = 1, 0.5%): dizziness (N = 1, 0.5%); nausea (N = 1, 0.5%).

  • Aliskiren 150 mg (N = 0).

  • Aliskiren 300 mg (N = 8, 4.4%): angina pectoris (N = 1, 0.6%); asthenia (N = 2, 1.1%); cough (N = 1, 0.6%); dizziness (N = 1, 0.6%); peripheral oedema (N = 1, 0.6%); emotional disorder (N = 1, 0.6%); fatigue (N = 1, 0.6%); headache (N = 1, 0.6%).

Additionally four patients discontinued from the study due to abnormal laboratory values.

  • Placebo (N = 1,Day 43): asymptomatic low white blood cell count.

  • Aliskiren 75 mg (N = 1, Day 15): abnormal ranges found for haematology and chemistry parameters.

  • Aliskiren 150 mg (N = 1, Day 6): elevated cholesterol and liver enzymes.

  • Aliskiren/HCTZ 150 25 mg/25 mg (N=1, Day 9): elevated cholesterol, BUN, uric acid.

CSPP100A2308

Most frequent reasons for 9 discontinuation from study: headache (N = 4), dizziness (N = 3), and diarrhoea (N = 2).

Reasons for discontinuations from AE (safety population).

  • Headache (placebo: N = 4); dizziness (placebo; N = 2; aliskiren 300 mg; 1), diarrhoea (placebo: N = 1; aliskiren 600 mg: N = 1); increased blood pressure (1 in placebo group); duodenal ulcer (placebo: N = 1); hypotension (placebo: N = 1); lethargy (placebo: N = 1); muscle spasm (placebo: N = 1); nausea (placebo: N = 1); and urticaria (placebo: N = 1); flatulence (aliskiren 600 mg: N = 1); altered mood (aliskiren 300 mg: N = 1); rash (aliskiren 300 mg: N = 1); and sense of oppression (aliskiren 150 mg: N = 1).

  • No patients were discontinued for abnormal laboratory values.

We question that a participant withdrew for the reason specified as "unsatisfactory effect" as opposed to being categorized as a discontinuation from an SAE as the event necessitated hospitalization. On Day 27 in CSPP100A2308, the participant (N = 1, 64F, aliskiren 150 mg) was hospitalized for unstable angina and increased blood pressure. The unstable angina was treated with concomitant medication and her condition resolved within 3 days.

CSPP100A2323

We do not have data at week 3 and week 6 for this study.

CSPP100A2327

The range of AEs resulting in study discontinuation is 8 (1.8%) is the aliskiren arm; 8 (2.6%) in valsartan arm; 6 (1.3%) in aliskiren/valsartan combination arm; and 11 (2.4%) in the placebo arm.

Reasons for discontinuations from adverse events ‐ N = 37 (2%).

  • Placebo (N = 11, 2.4%): headache (N = 4, 0.9%); nausea (N = 1, 0.2%); dyspnoea (N = 1, 0.2%); atrial flutter (N = 1, 0.2%); dizziness (N = 1, 0.2%); epistaxis (N = 1, 0.2%): hypertension (N = 1, 0.2%); hypertensive crisis (N = 1, 0.2%); peripheral oedema (N = 1, 0.2%).

  • Aliskiren = 8 (1.8%): blood pressure increased (N =1, 0.2%); gastritis (N =1, 0.2%); grand mal convulsion (N = 1, 0.2%); headache (N = 1, 0.2%); myocardial infarction (N = 2, 0.5%); non‐cardiac chest pain (N = 2, 0.5%); acute renal failure (N = 1, 0.2%).

CSPP100A2328

Aliskiren 75 mg = 3 (2.0%); aliskiren 150 mg = 5 (2.9%); aliskiren 300 mg = 4(2.5%) .

Placebo = 4 (2.5%). Reasons for withdrawal were not reported.

CSPP100A2405:

Reasons for 18 discontinuations from AE (safety population)

  • Placebo (N = 7, 3.8%): hypertension (N = 5, 2.7%); hypertensive crisis (N = 1, 0.5%); gastroenteritis (N = 1, 0.5%).

  • Aliskiren 75 mg (N = 7, 3.7%): hypertension (N = 1, 0.5%); headache (N = 1, 0.5%); dizziness (N = 2, 1.0%); hypertensive crisis (N = 1, 0.5%); dyspepsia (N = 1, 0.5%); nausea (N = 1, 0.5%).

  • Aliskiren 150 mg (N = 1); hypertension (N = 1).

  • Aliskiren 300 mg (N = 3): hypertension (N = 2, 1.1%),;headache (N = 1, 0.5%); vertigo (N = 1, 0.5%)

Figuras y tablas -
Table 10. Listing reasons for withdrawal due to adverse events
Ir a la tabla de la revisión
Comparison 1. Aliskiren vs. placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Systolic BP Show forest plot

12

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

1.1 Aliskiren 75 mg vs. placebo

5

1100

Mean Difference (IV, Fixed, 95% CI)

‐2.97 [‐4.76, ‐1.18]

1.2 Aliskiren 150 mg vs. placebo

12

3786

Mean Difference (IV, Fixed, 95% CI)

‐5.95 [‐6.85, ‐5.06]

1.3 Aliskiren 300 mg vs. placebo

10

3009

Mean Difference (IV, Fixed, 95% CI)

‐7.88 [‐8.94, ‐6.82]

1.4 Aliskiren 600 mg vs. placebo

2

393

Mean Difference (IV, Fixed, 95% CI)

‐11.35 [‐14.43, ‐8.27]

2 Diastolic BP Show forest plot

12

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

2.1 Aliskiren 75 mg vs placebo

5

1100

Mean Difference (IV, Fixed, 95% CI)

‐2.05 [‐3.13, ‐0.96]

2.2 Aliskiren 150 mg vs placebo

12

3783

Mean Difference (IV, Fixed, 95% CI)

‐3.16 [‐3.74, ‐2.58]

2.3 Aliskiren 300 mg vs placebo

10

3001

Mean Difference (IV, Fixed, 95% CI)

‐4.49 [‐5.17, ‐3.82]

2.4 Aliskiren 600 mg vs placebo

2

393

Mean Difference (IV, Fixed, 95% CI)

‐5.86 [‐7.73, ‐3.99]

3 Withdrawals due to adverse event Show forest plot

12

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 75 mg vs. placebo

5

1653

Risk Ratio (M‐H, Fixed, 95% CI)

0.59 [0.33, 1.07]

3.2 150 mg vs. placebo

10

3421

Risk Ratio (M‐H, Fixed, 95% CI)

0.46 [0.30, 0.71]

3.3 300 mg vs. placebo

10

4216

Risk Ratio (M‐H, Fixed, 95% CI)

0.70 [0.47, 1.03]

3.4 600 mg vs placebo

2

592

Risk Ratio (M‐H, Fixed, 95% CI)

0.56 [0.19, 1.64]

4 Cough Show forest plot

5

2886

Risk Ratio (M‐H, Fixed, 95% CI)

1.14 [0.49, 2.64]

5 Diarrhoea Show forest plot

7

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

5.1 Aliskiren 75 mg

4

1276

Risk Ratio (M‐H, Fixed, 95% CI)

2.21 [0.85, 5.76]

5.2 Aliskiren 150 mg

7

2277

Risk Ratio (M‐H, Fixed, 95% CI)

1.64 [0.78, 3.46]

5.3 Aliskiren 300 mg

7

2268

Risk Ratio (M‐H, Fixed, 95% CI)

1.84 [0.89, 3.81]

5.4 Aliskiren 600 mg

2

592

Risk Ratio (M‐H, Fixed, 95% CI)

7.00 [2.48, 19.72]
Figuras y tablas -
Comparison 1. Aliskiren vs. placebo
Ir a la tabla de la revisión
Comparison 2. Aliskiren150 mg vs. Aliskiren 75 mg

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Systolic BP Show forest plot

5

1651

Mean Difference (IV, Fixed, 95% CI)

‐1.89 [‐3.16, ‐0.62]

2 Diastolic BP Show forest plot

5

1651

Mean Difference (IV, Fixed, 95% CI)

‐0.80 [‐1.58, ‐0.03]
Figuras y tablas -
Comparison 2. Aliskiren150 mg vs. Aliskiren 75 mg
Ir a la tabla de la revisión
Comparison 3. Aliskiren 300 mg Vs. Aliskiren 75 mg

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 SBP Show forest plot

3

904

Mean Difference (IV, Fixed, 95% CI)

‐5.10 [‐6.79, ‐3.40]

2 DBP Show forest plot

3

904

Mean Difference (IV, Fixed, 95% CI)

‐2.49 [‐3.53, ‐1.45]
Figuras y tablas -
Comparison 3. Aliskiren 300 mg Vs. Aliskiren 75 mg
Ir a la tabla de la revisión
Comparison 4. Aliskiren 300 mg vs. Aliskiren 150 mg

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Systolic BP Show forest plot

10

4405

Mean Difference (IV, Fixed, 95% CI)

‐2.62 [‐3.38, ‐1.87]

2 Diastolic BP Show forest plot

10

4405

Mean Difference (IV, Fixed, 95% CI)

‐1.80 [‐2.28, ‐1.32]
Figuras y tablas -
Comparison 4. Aliskiren 300 mg vs. Aliskiren 150 mg
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Comparison 5. Aliskiren 600 mg vs. Aliskiren 150 mg

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 SBP Show forest plot

2

590

Mean Difference (IV, Fixed, 95% CI)

‐3.40 [‐5.58, ‐1.23]

2 DBP Show forest plot

2

590

Mean Difference (IV, Fixed, 95% CI)

‐2.20 [‐3.55, ‐0.85]
Figuras y tablas -
Comparison 5. Aliskiren 600 mg vs. Aliskiren 150 mg
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Comparison 6. Aliskiren 600 mg vs. Aliskiren 300 mg

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Systolic BP Show forest plot

2

592

Mean Difference (IV, Fixed, 95% CI)

‐0.61 [‐2.78, 1.56]

2 Diastolic BP Show forest plot

2

592

Mean Difference (IV, Fixed, 95% CI)

‐0.68 [‐2.03, 0.67]
Figuras y tablas -
Comparison 6. Aliskiren 600 mg vs. Aliskiren 300 mg
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