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Estatinas para el síndrome coronario agudo
Noah Vale, Alain J Nordmann, Gregory G Schwartz, James de Lemos, Furio Colivicchi, Frank den Hartog, Petr Ostadal, Stella M Macin, Anho H Liem, Edward J Mills, Neera Bhatnagar, Heiner C Bucher, Matthias Briel | 1 septiembre 2014

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Figure 1. Homocysteine metabolism (Reproduced with Dr Félix TM's permission from Brustolin 2010).
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Figure 1

Figure 1. Homocysteine metabolism (Reproduced with Dr Félix TM's permission from Brustolin 2010).

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Figure 2. Study flow diagram for this update.
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Figure 2

Figure 2. Study flow diagram for this update.

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Figure 3. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
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Figure 3

Figure 3. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Figure 4. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
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Figure 4

Figure 4. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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Figure 5. Trial sequential analysis of homocysteine lowering interventions versus placebo on myocardial infarction based on the diversity‐adjusted required information size (DARIS) of 10888 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) not crossed the conventional alpha of 5%. After the four 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 for disproving an intervention effect of 20% relative risk reduction. Smaller risk reductions might still require further higher trials.
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Figure 5

Figure 5. Trial sequential analysis of homocysteine lowering interventions versus placebo on myocardial infarction based on the diversity‐adjusted required information size (DARIS) of 10888 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) not crossed the conventional alpha of 5%. After the four 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 for disproving an intervention effect of 20% relative risk reduction. Smaller risk reductions might still require further higher trials.

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Figure 6. 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.
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Figure 6

Figure 6. 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.

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Figure 7. Trial sequential analysis of homocysteine lowering interventions versus placebo on stroke based on the diversity‐adjusted required information size (DARIS) of 17679 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) crosses temporally 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 for disproving an intervention effect of 20% relative risk reduction. Smaller risk reductions might still require further trials.
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Figure 7

Figure 7. Trial sequential analysis of homocysteine lowering interventions versus placebo on stroke based on the diversity‐adjusted required information size (DARIS) of 17679 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) crosses temporally 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 for disproving an intervention effect of 20% relative risk reduction. Smaller risk reductions might still require further trials.

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Figure 8. 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.
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Figure 8

Figure 8. 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.

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Figure 9. Trial sequential analysis of homocysteine lowering interventions versus placebo on death by any cause based on the diversity‐adjusted required information size (DARIS) of 1049 patients. This DARIS was calculated based upon a proportion of death by any cause out of 13% in the control group; a RRR of 12% in the experimental intervention group; an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 16%. After third trial, the cumulative Z‐curve (blue line) crossed 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 for disproving an intervention effect of 15% relative risk reduction. Smaller risk reductions might still require further trials.
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Figure 9

Figure 9. Trial sequential analysis of homocysteine lowering interventions versus placebo on death by any cause based on the diversity‐adjusted required information size (DARIS) of 1049 patients. This DARIS was calculated based upon a proportion of death by any cause out of 13% in the control group; a RRR of 12% in the experimental intervention group; an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 16%. After third trial, the cumulative Z‐curve (blue line) crossed 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 for disproving an intervention effect of 15% relative risk reduction. Smaller risk reductions might still require further trials.

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Figure 10. Funnel plot of data from the meta‐analysis of the effects of homocysteine lowering interventions for preventing death by 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.
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Figure 10

Figure 10. Funnel plot of data from the meta‐analysis of the effects of homocysteine lowering interventions for preventing death by 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.

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Figure 11. Trial sequential analysis of homocysteine lowering interventions versus placebo on adverse events (cancer) based on the diversity‐adjusted required information size (DARIS) of 17676 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 an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 0%. The cumulative Z‐curve (blue line) crossed the trials sequential beta‐spending monitoring boundary, showing that the area of futility has been reached. This suggest that no more trials are needed for disproving an intervention effect of 13% relative risk reduction.
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Figure 11

Figure 11. Trial sequential analysis of homocysteine lowering interventions versus placebo on adverse events (cancer) based on the diversity‐adjusted required information size (DARIS) of 17676 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 an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 0%. The cumulative Z‐curve (blue line) crossed the trials sequential beta‐spending monitoring boundary, showing that the area of futility has been reached. This suggest that no more trials are needed for disproving an intervention effect of 13% relative risk reduction.

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Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 1 Myocardial infarction.
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Analysis 1.1

Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 1 Myocardial infarction.

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Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 2 Stroke.
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Analysis 1.2

Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 2 Stroke.

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Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 3 First unstable angina pectoris episode requiring hospitalization.
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Analysis 1.3

Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 3 First unstable angina pectoris episode requiring hospitalization.

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Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 4 Death by any cause.
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Analysis 1.4

Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 4 Death by any cause.

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Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 5 Serious adverse events (Cancer).
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Analysis 1.5

Comparison 1 Homocysteine‐lowering treatment versus other (any comparisons), Outcome 5 Serious adverse events (Cancer).

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Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 1 Myocardial infarction.
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Analysis 2.1

Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 1 Myocardial infarction.

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Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 2 Stroke.
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Analysis 2.2

Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 2 Stroke.

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Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 3 First unstable angina pectoris episode requiring hospitalisation.
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Analysis 2.3

Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 3 First unstable angina pectoris episode requiring hospitalisation.

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Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 4 Death by any cause.
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Analysis 2.4

Comparison 2 Homocysteine‐lowering treatment versus other (Sensitivity analysis), Outcome 4 Death by any cause.

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Summary of findings for the main comparison. Homocysteine‐lowering interventions (Folic Acid, Vitamin B6 and Vitamin B12) compared to placebo or standard care for preventing cardiovascular events

Homocysteine‐lowering interventions (Folic acid, vitamin B6 and vitamin B12) compared to placebo or standard care for preventing cardiovascular events

Patient or population: patients with preventing cardiovascular events
Settings:
Intervention: homocysteine‐lowering interventions (Folic acid, vitamin B6 and vitamin B12)
Comparison: placebo or standard care

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo or standard care

Homocysteine‐lowering interventions (Folic acid, vitamin B6 and vitamin B12)

Myocardial infarction (non‐fatal or fatal)
Follow‐up: 1 to 7.3 years

Study population

RR 1.02
(0.95 to 1.1)

43290
(10 studies)

⊕⊕⊕⊕
high1,2

62 per 1000

64 per 1000
(59 to 69)

Low

62 per 1000

63 per 1000
(59 to 68)

Stroke
Follow‐up: 1 to 7.3 years

Study population

RR 0.91
(0.82 to 1.01)

40815
(8 studies)

⊕⊕⊕⊕
high3,4

52 per 1000

47 per 1000
(43 to 52)

Moderate

Death by any cause
Follow‐up: 1 to 7.3 years

Study population

RR 1.01
(0.96 to 1.07)

41898
(10 studies)

⊕⊕⊕⊕
high5,6

130 per 1000

131 per 1000
(125 to 139)

Moderate

Cancer
Follow‐up: 3.4 to 7.3 years

Study population

RR 1.06
(0.98 to 1.13)

32869
(7 studies)

⊕⊕⊕⊕
high7,8

91 per 1000

96 per 1000
(89 to 102)

Moderate

*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;

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 I‐squared: 0%
2 43290 participants with 2986 events
3 I‐squared: 13%
4 40815 participants with 1940 events
5 I‐squared: 6%
6 41898 participants with 5286 events
7 I‐squared: 0%
8 32869 participants with 2892 events

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Summary of findings for the main comparison. Homocysteine‐lowering interventions (Folic Acid, Vitamin B6 and Vitamin B12) compared to placebo or standard care for preventing cardiovascular events
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Comparison 1. Homocysteine‐lowering treatment versus other (any comparisons)

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 hospitalization Show forest plot

4

12644

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.80, 1.21]

4 Death by 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]
Figuras y tablas -
Comparison 1. Homocysteine‐lowering treatment versus other (any comparisons)
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Comparison 2. Homocysteine‐lowering treatment versus other (Sensitivity analysis)

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 by 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]
Figuras y tablas -
Comparison 2. Homocysteine‐lowering treatment versus other (Sensitivity analysis)
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