Homocysteine‐lowering interventions for preventing cardiovascular events
Information
- DOI:
- https://doi.org/10.1002/14651858.CD006612.pub4Copy DOI
- Database:
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- Cochrane Database of Systematic Reviews
- Version published:
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- 15 January 2015see what's new
- Type:
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- Intervention
- Stage:
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- Review
- Cochrane Editorial Group:
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Cochrane Heart Group
- Copyright:
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- Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Authors
Contributions of authors
Arturo Marti‐Carvajal took the lead on writing up the Cochrane Review.
Ivan Solà identified trials, extracted data, edited the 'Summary of findings' table and drafted the Cochrane Review.
Dimitris Lathyris extracted and checked the data and reviewed the Cochrane Review.
Sources of support
Internal sources
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No sources of support supplied
External sources
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Iberoamerican Cochrane Centre, Spain.
Academic
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Cochrane Heart Group, UK.
Academic
Declarations of interest
Ivan Solà and Dimitrios Lathyris: none known.
In 2004 Arturo Martí‐Carvajal was employed by Eli Lilly to run a four‐hour workshop on 'How to critically appraise clinical trials on osteoporosis and how to teach this'. This activity was not related to his work with The Cochrane Collaboration or any Cochrane Review.
In 2007 Arturo Martí‐Carvajal was employed by Merck to run a four‐hour workshop 'How to critically appraise clinical trials and how to teach this'. This activity was not related to his work with The Cochrane Collaboration or any Cochrane Review.
Acknowledgements
We express our gratitude to the Cochrane Heart Group and peer referees for the suggestions made to enhance the quality of this review. In addition, we acknowledge Dr Temis Maria Felix for giving us permission to publish Figure 1 from Brustolin 2010, and to Carmen Verônica Abdala from BIREME/OPS/OMS for her help in developing the search strategy for LILACS. In addition, we want express our deep gratitude to Georgia Salanti for teaching us how to conduct the first version of this Cochrane Review.
Version history
Published | Title | Stage | Authors | Version |
2017 Aug 17 | Homocysteine‐lowering interventions for preventing cardiovascular events | Review | Arturo J Martí-Carvajal, Ivan Solà, Dimitrios Lathyris, Mark Dayer | |
2015 Jan 15 | Homocysteine‐lowering interventions for preventing cardiovascular events | Review | Arturo J Martí‐Carvajal, Ivan Solà, Dimitrios Lathyris | |
2013 Jan 31 | Homocysteine‐lowering interventions for preventing cardiovascular events | Review | Arturo J Martí‐Carvajal, Ivan Solà, Dimitrios Lathyris, Despoina‐Elvira Karakitsiou, Daniel Simancas‐Racines | |
2009 Oct 07 | Homocysteine lowering interventions for preventing cardiovascular events | Review | Arturo J Martí‐Carvajal, Ivan Solà, Dimitrios Lathyris, Georgia Salanti | |
2009 Jul 08 | Homocysteine lowering interventions for preventing cardiovascular events | Protocol | Arturo J Martí‐Carvajal, Georgia Salanti, Ricardo Hidalgo, Agustín Ciapponi | |
Differences between protocol and review
This update includes a trial sequential analysis.
In the first version of the review (Marti‐Carvajal 2009), we searched the Allied and Complementary Medicine ‐ AMED database (accessed through Ovid) and the Cochrane Stroke Group Specialised Register. For this update, we did not search either database.
This update includes the Plain Summary Language 'section' adapted according to the new recommendations of The Cochrane Collaboration. The results include the quality of the evidence assessed according to GRADE ('Summary of findings').
Keywords
MeSH
Medical Subject Headings (MeSH) Keywords
- Angina Pectoris [prevention & control];
- Cardiovascular Diseases [etiology, *prevention & control];
- Cause of Death;
- Folic Acid [therapeutic use];
- Hyperhomocysteinemia [complications, *therapy];
- Myocardial Infarction [epidemiology, prevention & control];
- Randomized Controlled Trials as Topic;
- Risk Factors;
- Stroke [epidemiology, prevention & control];
- Vitamin B 12 [therapeutic use];
- Vitamin B 6 [therapeutic use];
- Vitamin B Complex [*therapeutic use];
Medical Subject Headings Check Words
Humans;
PICOs
![Homocysteine metabolism (Reproduced with Dr Félix TM's permission from Brustolin 2010)](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-AFig-FIG01.png)
Homocysteine metabolism (Reproduced with Dr Félix TM's permission from Brustolin 2010)
![Study flow diagram for this update](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-AFig-FIG02.png)
Study flow diagram for this update
![Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-AFig-FIG03.png)
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies
![Methodological quality summary: review authors' judgements about each methodological quality item for each included study](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-AFig-FIG04.png)
Methodological quality summary: review authors' judgements about each methodological quality item for each included study
![Trial sequential analysis on myocardial infarction in 11 trials investigating homocysteine‐lowering interventions versus placebo Trial sequential analysis of homocysteine‐lowering interventions versus placebo on myocardial infarction based on the diversity‐adjusted required information size (DARIS) of 10,888 patients. This DARIS was calculated based upon a proportion of patients with myocardial infarction of 6.17% in the control group; a RRR of 20% in the experimental intervention group; an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 0%. The cumulative Z‐curve (blue line) does not cross the conventional alpha of 5%. After the fourth trial, the cumulative Z‐curve crosses the trial sequential beta‐spending monitoring boundary, showing that the area of futility has been reached. This suggests that no more trials may be needed to disprove an intervention effect of 20% relative risk reduction. Smaller risk reductions might still require further trials.](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-AFig-FIG05.png)
Trial sequential analysis on myocardial infarction in 11 trials investigating homocysteine‐lowering interventions versus placebo
Trial sequential analysis of homocysteine‐lowering interventions versus placebo on myocardial infarction based on the diversity‐adjusted required information size (DARIS) of 10,888 patients. This DARIS was calculated based upon a proportion of patients with myocardial infarction of 6.17% in the control group; a RRR of 20% in the experimental intervention group; an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 0%. The cumulative Z‐curve (blue line) does not cross the conventional alpha of 5%. After the fourth trial, the cumulative Z‐curve crosses the trial sequential beta‐spending monitoring boundary, showing that the area of futility has been reached. This suggests that no more trials may be needed to disprove an intervention effect of 20% relative risk reduction. Smaller risk reductions might still require further trials.
![Funnel plot of data from the meta‐analysis of the effects of homocysteine‐lowering interventions for preventing myocardial infarction The circles show the point estimates of the included randomised clinical trials. The pattern of distribution resembles an inverted funnel. Larger trials are upper and closer to the pooled estimate. The effect sizes of the smaller studies are more or less symmetrically distributed around the pooled estimate. This figure shows a low risk of publication bias.](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-AFig-FIG06.png)
Funnel plot of data from the meta‐analysis of the effects of homocysteine‐lowering interventions for preventing myocardial infarction
The circles show the point estimates of the included randomised clinical trials. The pattern of distribution resembles an inverted funnel. Larger trials are upper and closer to the pooled estimate. The effect sizes of the smaller studies are more or less symmetrically distributed around the pooled estimate. This figure shows a low risk of publication bias.
![Trial sequential analysis on stroke in nine trials investigating homocysteine‐lowering interventions versus placebo Trial sequential analysis of homocysteine‐lowering interventions versus placebo on stroke based on the diversity‐adjusted required information size (DARIS) of 17,679 patients. This DARIS was calculated based upon a proportion of patients with stroke of 5.13% in the control group; a RRR of 20% in the experimental intervention group; an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 26%. The cumulative Z‐curve (blue line) temporally crosses the conventional alpha of 5%, but reverts to insignificant values. The cumulative Z‐curve never crosses the trial sequential alpha‐spending monitoring boundaries. After the third trial, the cumulative Z‐curve crosses the trial sequential beta‐spending monitoring boundary, showing that the area of futility has been reached. This suggests that no more trials may be needed to disprove an intervention effect of 20% relative risk reduction. Smaller risk reductions might still require further trials.](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-AFig-FIG07.png)
Trial sequential analysis on stroke in nine trials investigating homocysteine‐lowering interventions versus placebo
Trial sequential analysis of homocysteine‐lowering interventions versus placebo on stroke based on the diversity‐adjusted required information size (DARIS) of 17,679 patients. This DARIS was calculated based upon a proportion of patients with stroke of 5.13% in the control group; a RRR of 20% in the experimental intervention group; an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 26%. The cumulative Z‐curve (blue line) temporally crosses the conventional alpha of 5%, but reverts to insignificant values. The cumulative Z‐curve never crosses the trial sequential alpha‐spending monitoring boundaries. After the third trial, the cumulative Z‐curve crosses the trial sequential beta‐spending monitoring boundary, showing that the area of futility has been reached. This suggests that no more trials may be needed to disprove an intervention effect of 20% relative risk reduction. Smaller risk reductions might still require further trials.
![Funnel plot of data from the meta‐analysis of the effects of homocysteine‐lowering interventions for preventing stroke The circles show the point estimates of the included randomised clinical trials. The pattern of distribution resembles an inverted funnel. Larger trials are closer and upper to the pooled estimate. The effect sizes of the smaller trials are lower and more or less symmetrically distributed around the pooled estimate. This figure shows a low risk of publication bias.](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-AFig-FIG08.png)
Funnel plot of data from the meta‐analysis of the effects of homocysteine‐lowering interventions for preventing stroke
The circles show the point estimates of the included randomised clinical trials. The pattern of distribution resembles an inverted funnel. Larger trials are closer and upper to the pooled estimate. The effect sizes of the smaller trials are lower and more or less symmetrically distributed around the pooled estimate. This figure shows a low risk of publication bias.
![Trial sequential analysis on death from any cause in 10 trials investigating homocysteine‐lowering interventions versus placebo Trial sequential analysis of homocysteine‐lowering interventions versus placebo on death from any cause based on the diversity‐adjusted required information size (DARIS) of 10,419 patients. This DARIS was calculated based upon a proportion of death from any cause out of 13% in the control group; a RRR of 15% in the experimental intervention group; an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 16%. After the third trial, the cumulative Z‐curve (blue line) crosses the trial sequential beta‐spending monitoring boundary, showing that the area of futility has been reached. This suggests that no more trials may be needed to disprove an intervention effect of 15% relative risk reduction. Smaller risk reductions might still require further trials.](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-AFig-FIG09.png)
Trial sequential analysis on death from any cause in 10 trials investigating homocysteine‐lowering interventions versus placebo
Trial sequential analysis of homocysteine‐lowering interventions versus placebo on death from any cause based on the diversity‐adjusted required information size (DARIS) of 10,419 patients. This DARIS was calculated based upon a proportion of death from any cause out of 13% in the control group; a RRR of 15% in the experimental intervention group; an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 16%. After the third trial, the cumulative Z‐curve (blue line) crosses the trial sequential beta‐spending monitoring boundary, showing that the area of futility has been reached. This suggests that no more trials may be needed to disprove an intervention effect of 15% relative risk reduction. Smaller risk reductions might still require further trials.
![Funnel plot of data from the meta‐analysis of the effects of homocysteine‐lowering interventions for preventing death from any cause This figure shows a low risk of publication bias. The circles show the point estimates of the included randomised clinical trials. The pattern of distribution simulates an inverted funnel. Larger trials are closer and upper to the pooled estimate. The effect sizes of the smaller trials are lower and more or less symmetrically distributed around the pooled estimate. This figure shows a low risk of publication bias.](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-AFig-FIG10.png)
Funnel plot of data from the meta‐analysis of the effects of homocysteine‐lowering interventions for preventing death from any cause
This figure shows a low risk of publication bias. The circles show the point estimates of the included randomised clinical trials. The pattern of distribution simulates an inverted funnel. Larger trials are closer and upper to the pooled estimate. The effect sizes of the smaller trials are lower and more or less symmetrically distributed around the pooled estimate. This figure shows a low risk of publication bias.
![Trial sequential analysis on adverse events (cancer) in seven trials investigating homocysteine‐lowering interventions versus placebo Trial sequential analysis of homocysteine‐lowering interventions versus placebo on adverse events (cancer) based on the diversity‐adjusted required information size (DARIS) of 17,676 patients. This DARIS was calculated based upon a proportion of patients developing cancer of 9% in the control group; a RRR of 13% in the experimental intervention group; an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 0%. The cumulative Z‐curve (blue line) crosses the trials sequential beta‐spending monitoring boundary, showing that the area of futility has been reached. This suggests that no more trials are needed to disprove an intervention effect of 13% relative risk reduction.](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-AFig-FIG11.png)
Trial sequential analysis on adverse events (cancer) in seven trials investigating homocysteine‐lowering interventions versus placebo
Trial sequential analysis of homocysteine‐lowering interventions versus placebo on adverse events (cancer) based on the diversity‐adjusted required information size (DARIS) of 17,676 patients. This DARIS was calculated based upon a proportion of patients developing cancer of 9% in the control group; a RRR of 13% in the experimental intervention group; an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 0%. The cumulative Z‐curve (blue line) crosses the trials sequential beta‐spending monitoring boundary, showing that the area of futility has been reached. This suggests that no more trials are needed to disprove an intervention effect of 13% relative risk reduction.
![Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 1 Myocardial infarction.](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-CMP-001-01.png)
Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 1 Myocardial infarction.
![Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 2 Stroke.](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-CMP-001-02.png)
Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 2 Stroke.
![Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 3 First unstable angina pectoris episode requiring hospitalisation.](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-CMP-001-03.png)
Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 3 First unstable angina pectoris episode requiring hospitalisation.
![Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 4 Death from any cause.](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-CMP-001-04.png)
Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 4 Death from any cause.
![Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 5 Serious adverse events (cancer).](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-CMP-001-05.png)
Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 5 Serious adverse events (cancer).
![Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 1 Myocardial infarction.](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-CMP-002-01.png)
Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 1 Myocardial infarction.
![Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 2 Stroke.](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-CMP-002-02.png)
Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 2 Stroke.
![Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 3 First unstable angina pectoris episode requiring hospitalisation.](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-CMP-002-03.png)
Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 3 First unstable angina pectoris episode requiring hospitalisation.
![Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 4 Death from any cause.](https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub4/media/CDSR/CD006612/rel0004/CD006612/image_n/nCD006612-CMP-002-04.png)
Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 4 Death from any cause.
Homocysteine‐lowering interventions (folic acid, vitamin B6 and vitamin B12) compared with placebo or standard care for preventing cardiovascular events | ||||||
Patient or population: Adults at risk of or with established cardiovascular disease | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Placebo or standard care | Homocysteine‐lowering interventions (folic acid, vitamin B6 and vitamin B12) | |||||
Non‐fatal or fatal myocardial infarction | Study population | RR 1.02 | 43,290 | ⊕⊕⊕⊕ | ||
62 per 1000 | 64 per 1000 | |||||
Stroke | Study population | RR 0.91 | 40,815 | ⊕⊕⊕⊕ | ||
52 per 1000 | 47 per 1000 | |||||
Death from any cause | Study population | RR 1.01 | 41,898 | ⊕⊕⊕⊕ | ||
130 per 1000 | 131 per 1000 | |||||
Cancer | Study population | RR 1.06 | 32,869 | ⊕⊕⊕⊕ | ||
91 per 1000 | 96 per 1000 | |||||
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1I² = 0%. |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Myocardial infarction Show forest plot | 12 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
1.1 Homocysteine‐lowering versus placebo | 11 | 43780 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.95, 1.10] |
1.2 Homocysteine‐lowering treatment at high dose versus low dose | 1 | 3649 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.66, 1.23] |
2 Stroke Show forest plot | 10 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
2.1 Homocysteine‐lowering treatment versus placebo | 9 | 41305 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.82, 1.00] |
2.2 Homocysteine‐lowering treatment at high dose versus low dose | 1 | 3649 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.84, 1.29] |
3 First unstable angina pectoris episode requiring hospitalisation Show forest plot | 4 | 12644 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.80, 1.21] |
4 Death from any cause Show forest plot | 11 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
4.1 Homocysteine‐lowering treatment versus placebo | 10 | 41898 | Risk Ratio (M‐H, Random, 95% CI) | 1.01 [0.96, 1.07] |
4.2 Homocysteine‐lowering treatments at high dose versus low dose | 1 | 3649 | Risk Ratio (M‐H, Random, 95% CI) | 0.86 [0.66, 1.11] |
5 Serious adverse events (cancer) Show forest plot | 7 | 32869 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.98, 1.13] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Myocardial infarction Show forest plot | 7 | 40532 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.95, 1.09] |
1.1 Trials with low risk of bias (mixed populations) | 6 | 35090 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.95, 1.10] |
1.2 Trials with low risk of bias (only women included) | 1 | 5442 | Risk Ratio (M‐H, Random, 95% CI) | 0.88 [0.63, 1.22] |
2 Stroke Show forest plot | 7 | 40532 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.81, 1.01] |
2.1 Trials with low risk of bias (mixed populations) | 6 | 35090 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.81, 0.98] |
2.2 Trials with low risk of bias (only women included) | 1 | 5442 | Risk Ratio (M‐H, Random, 95% CI) | 1.14 [0.83, 1.57] |
3 First unstable angina pectoris episode requiring hospitalisation Show forest plot | 3 | 12361 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.79, 1.24] |
4 Death from any cause Show forest plot | 8 | 41022 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.95, 1.12] |
4.1 Trials with low risk of bias (mixed populations) | 7 | 35580 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.95, 1.15] |
4.2 Trials with low risk of bias (only women included) | 1 | 5442 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.83, 1.15] |