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Homocysteine‐lowering interventions for preventing cardiovascular events

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Appendices

Appendix 1. Burden of deaths attributable to cardiovascular diseases (%) (from Gaziano 2006)

Region

%

Sub‐Saharan Africa, parts of all regions excluding high‐income regions

5 to 10

South Asia, southern East Asia and the Pacific, parts of Latin America and the Caribbean

15 to 35

Europe and Central Asia, northern East Asia and the Pacific, Latin America and the Caribbean,

Middle East and North Africa, and urban parts of most low‐income regions (especially India)

> 50

High‐income countries, parts of Latin America and the Caribbean

< 50

Appendix 2. Search strategies 2008

CENTRAL

#1 MeSH descriptor Vitamin B Complex explode all trees
#2 ”vitamin b*“
#3 folic next acid in Title, Abstract or Keywords
#4 folate* in Title, Abstract or Keywords
#5 (homocyst* near/6 lower*)
#6 (homocyst* near/6 reduc*)
#7 pyridoxin*
#8 cobalamin*
#9 cyanocobalamin*
#10 pyridoxol*
#11 MeSH descriptor Vitamins this term only
#12 (vitamin* and homocyst*)
#13 multivitamin*
#14 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13)
#15 MeSH descriptor Cardiovascular Diseases this term only
#16 MeSH descriptor Myocardial Ischemia explode all trees
#17 MeSH descriptor Brain Ischemia explode all trees
#18 MeSH descriptor Cerebrovascular Disorders this term only
#19 (coronary near/6 disease)
#20 angina
#21 myocardial next infarct*
#22 heart next infarct*
#23 (stroke or strokes)
#24 (cerebr* near/6 accident*)
#25 (cerebr* near/6 infarct*)
#26 (brain near/6 infarct*)
#27 apoplexy
#28 cardiovascular next disease*
#29 (cardiovascular near/6 event*)
#30 MeSH descriptor Hyperhomocysteinemia explode all trees
#31 hyperhomocyst*
#32 cva
#33 (#15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25)
#34 (#26 or #27 or #28 or #29 or #30 or #31 or #32)
#35 (#33 or #34)
#36 (#14 and #35)

LILACS (accessed through Biblioteca Virtual em Saúde)

((Pt ENSAYO CONTROLADO ALEATORIO OR Pt ENSAYO CLINICO CONTROLADO OR Mh ENSAYOS CONTROLADOS ALEATORIOS OR Mh DISTRIBUCIÓN ALEATORIA OR Mh METODO DOBLE CIEGO OR Mh METODO SIMPLECIEGO OR Pt ESTUDIO MULTICÉNTRICO) or ((tw ensaio or tw ensayo or tw trial) and (tw azar or tw acaso or tw placebo or tw control$ or tw aleat$ or tw random$ or (tw duplo and tw cego) or (tw doble and tw ciego) or (tw double and tw blind)) and tw clinic$)) AND NOT ((Ct ANIMALES OR Mh ANIMALES OR Ct CONEJOS OR Ct RATÓN OR MH Ratas OR MH Primates OR MH Perros OR MH Conejos OR MH Porcinos) AND NOT (Ct HUMANO AND Ct ANIMALES)) [Palavras] and MH Vitamina B 12 OR Cobamidas OR Hidroxocobalamina OR Complejo Vitamínico B OR Ácido Fólico OR Ácidos Pteroilpoliglutámicos OR Tetrahidrofolatos OR Formiltetrahidrofolatos OR Vitamina B 6 OR Piridoxal OR Fosfato de Piridoxal OR Piridoxamina OR Piridoxina OR Homocisteína OR Vitaminas or TW vitamin$ or tw cobalamin$ or tw cianocobalamin$ or tw cyanocobalam$ or tw cobamid$ or tw hidroxocobalam$ or tw Hydroxocobalam$ or ((tw complejo or tw complex$) and tw vitamin$ and tw b) or (tw acid$ and (tw folic$ or tw ptero$)) or tw Tetrahidrofolatos or tw Formiltetrahidrofolatos or (tw vitamin$ or (tw b or tw b6 or tw b12)) or tw Piridoxal or tw Pyridoxal or ((tw Fosfat$ or tw phosphate$) and (tw Piridoxal or tw pyridoxal)) or tw Piridox$ or tw Pyridox$ or tw Homocisteína or tw Homocysteine) AND (MH Enfermedades Cardiovasculares or Isquemia Miocárdica or Ex C14.280.647$ or Isquemia Encefálica or Ex C10.228.140.300.150$ or Trastornos Cerebrovasculares or hiperhomocisteinemia or Accidente Cerebrovascular or ((tw apoplexia or tw derrame or tw trastorno$ or tw accident$ or tw acidente or tw stroke$ or tw disease$ or tw enfermedad$ or tw doenca$ or tw event$ or tw infart$ or tw isquemia or tw disorder$) and (tw miocardio or tw myocard$ or tw cerebr$ or tw cardiovascul$ or tw heart or tw cardiovascul$ or tw encefal$)) or tw hyperhomocyst$ or tw hiperhomocisteinemia) [Palavras]

MEDLINE

1 exp Vitamin B Complex/
2 vitamin b.tw.
3 folic acid.tw.
4 folate$.tw.
5 ((homocystein$ or homocystin$) adj3 (low$ or reduc$)).tw.
6 pyridoxin$.tw.
7 cobalamin$.tw.
8 cyanocobalamin$.tw.
9 pyridoxol$.tw.
10 Vitamins/
11 or/1‐10
12 Cardiovascular Diseases/
13 exp Myocardial Ischemia/
14 exp Brain Ischemia/
15 Cerebrovascular Disorders/
16 (coronary adj3 disease$).tw.
17 angina.tw.
18 myocardial infarct$.tw.
19 heart infarct$.tw.
20 heart attack$.tw.
21 (stroke or strokes).tw.
22 (cerebr$ adj3 (accident$ or infarct$)).tw.
23 (brain adj3 infarct$).tw.
24 apoplexy.tw.
25 (cardiovascular adj2 (disease$ or event$)).tw.
26 Hyperhomocysteinemia/
27 hyperhomocyst?in?emi$.tw.
28 or/12‐27
29 11 and 28
30 randomized controlled trial.pt.
31 controlled clinical trial.pt.
32 Randomized controlled trials/
33 random allocation/
34 double blind method/
35 single‐blind method/
36 or/30‐35
37 exp animal/ not humans/
38 36 not 37
39 clinical trial.pt.
40 exp Clinical Trials as Topic/
41 (clin$ adj25 trial$).ti,ab.
42 ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ti,ab.
43 placebos/
44 placebo$.ti,ab.
45 random$.ti,ab.
46 research design/
47 or/39‐46
48 47 not 37
49 38 or 48
50 49 and 29

EMBASE

1 exp Vitamin B Group/
2 vitamin b.tw.
3 folic acid.tw.
4 folate$.tw.
5 ((homocystein$ or homocystin$) adj3 (low$ or reduc$)).tw.
6 pyridoxin$.tw.
7 cobalamin$.tw.
8 cyanocobalamin$.tw.
9 pyridoxol$.tw.
10 Vitamins/
11 or/1‐10
12 Cardiovascular Diseases/
13 exp ischaemic heart disease/
14 exp Coronary Artery Disease/
15 exp Brain Ischemia/
16 cerebrovascular disease/
17 stroke/
18 cerebrovascular accident/
19 (coronary adj3 disease$).tw.
20 angina.tw.
21 myocardial infarct$.tw.
22 heart infarct$.tw.
23 heart attack$.tw.
24 (stroke or strokes).tw.
25 (cerebr$ adj3 (accident$ or infarct$)).tw.
26 (brain adj3 infarct$).tw.
27 apoplexy.tw.
28 (cardiovascular adj2 (disease$ or event$)).tw.
29 Hyperhomocysteinemia/
30 hyperhomocyst?in?emi$.tw.
31 or/12‐30
32 11 and 31
33 controlled clinical trial/
34 random$.tw.
35 randomized controlled trial/
36 follow‐up.tw.
37 double blind procedure/
38 placebo$.tw.
39 placebo/
40 factorial$.ti,ab.
41 (crossover$ or cross‐over$).ti,ab.
42 (double$ adj blind$).ti,ab.
43 (singl$ adj blind$).ti,ab.
44 assign$.ti,ab.
45 allocat$.ti,ab.
46 volunteer$.ti,ab.
47 Crossover Procedure/
48 Single Blind Procedure/
49 or/33‐48
50 32 and 49

Web of Science

# 11 TS=(#10 and (random* or blind* or placebo* or comparative or comparison or prospective or controlled or trial or evaluation or rct))
# 10 #7 or #8 or #9
# 9 TS=(#6 and (”cerebrovascular accident*“ or hyperhomocyst*))
# 8 TS=(#6 and (angina or stroke or strokes or cva or infarction*))
# 7 TS=(#6 and (cardiovascular or myocardial or coronary or cardiac or ”heart disease*“))
# 6 #1 or #2 or #3 or #4 or #5
# 5 TS=(homocyst* same (lower* or reduc*))
# 4 TS=(vitamin* and homocyst*)
# 3 TS=folate*
# 2 TS=”vitamin B“
# 1 TS=(pyridoxin* or cobalamin* or cyanocobalamin* or pyridoxol* or ”folic acid“)

Appendix 3. Search strategies 2012

CENTRAL

#1 MeSH descriptor Vitamin B Complex explode all trees
#2 (vitamin b)
#3 folic acid
#4 folate*
#5 ((homocystein* or homocystin*) near/3 (low* or reduc*))
#6 (pyridoxin*)
#7 (cobalamin*)
#8 (cyanocobalamin*)
#9 (pyridoxol*)
#10 MeSH descriptor Vitamins, this term only
#11 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10)
#12 MeSH descriptor Cardiovascular Diseases, this term only
#13 MeSH descriptor Myocardial Ischemia explode all trees
#14 MeSH descriptor Brain Ischemia explode all trees
#15 MeSH descriptor Cerebrovascular Disorders, this term only
#16 (coronary near/3 disease*)
#17 (angina)
#18 (myocardial infarct*)
#19 (heart infarct*)
#20 (heart attack*)
#21 (stroke or strokes)
#22 (cerebr* near/3 (accident* or infarct*))
#23 (brain near/3 infarct*)
#24 (apoplexy)
#25 (cardiovascular near/2 (disease* or event*))
#26 MeSH descriptor Hyperhomocysteinemia, this term only
#27 hyperhomocyst?in?emi*
#28 (#12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27)
#29 (#11 AND #28)

MEDLINE

1 exp Vitamin B Complex/
2 vitamin b.tw.
3 folic acid.tw.
4 folate$.tw.
5 ((homocystein$ or homocystin$) adj3 (low$ or reduc$)).tw.
6 pyridoxin$.tw.
7 cobalamin$.tw.
8 cyanocobalamin$.tw.
9 pyridoxol$.tw.
10 Vitamins/
11 or/1‐10
12 Cardiovascular Diseases/
13 exp Myocardial Ischemia/
14 exp Brain Ischemia/
15 Cerebrovascular Disorders/
16 (coronary adj3 disease$).tw.
17 angina.tw.
18 myocardial infarct$.tw.
19 heart infarct$.tw.
20 heart attack$.tw.
21 (stroke or strokes).tw.
22 (cerebr$ adj3 (accident$ or infarct$)).tw.
23 (brain adj3 infarct$).tw.
24 apoplexy.tw.
25 (cardiovascular adj2 (disease$ or event$)).tw.
26 Hyperhomocysteinemia/
27 hyperhomocyst?in?emi$.tw.
28 or/12‐27
29 11 and 28
30 randomized controlled trial.pt.
31 controlled clinical trial.pt.
32 randomized.ab.
33 placebo.ab.
34 drug therapy.fs.
35 randomly.ab.
36 trial.ab.
37 groups.ab.
38 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37
39 exp animals/ not humans.sh. (3663238)
40 38 not 39
41 29 and 40
42 (200808* or 200809* or 20081* or 2009* or 2010* or 2011* or 2012*).ed.
43 41 and 42

EMBASE

1 exp Vitamin B Complex/
2 vitamin b.tw.
3 folic acid.tw.
4 folate$.tw.
5 ((homocystein$ or homocystin$) adj3 (low$ or reduc$)).tw.
6 pyridoxin$.tw.
7 cobalamin$.tw.
8 cyanocobalamin$.tw.
9 pyridoxol$.tw.
10 Vitamins/
11 or/1‐10
12 Cardiovascular Diseases/
13 exp Myocardial Ischemia/
14 exp Brain Ischemia/
15 Cerebrovascular Disorders/
16 (coronary adj3 disease$).tw.
17 angina.tw.
18 myocardial infarct$.tw.
19 heart infarct$.tw.
20 heart attack$.tw.
21 (stroke or strokes).tw.
22 (cerebr$ adj3 (accident$ or infarct$)).tw.
23 (brain adj3 infarct$).tw.
24 apoplexy.tw.
25 (cardiovascular adj2 (disease$ or event$)).tw.
26 Hyperhomocysteinemia/
27 hyperhomocyst?in?emi$.tw.
28 or/12‐27
29 11 and 28
30 random$.tw.
31 factorial$.tw.
32 crossover$.tw.
33 cross over$.tw.
34 cross‐over$.tw.
35 placebo$.tw.
36 (doubl$ adj blind$).tw.
37 (singl$ adj blind$).tw.
38 assign$.tw.
39 allocat$.tw.
40 volunteer$.tw.
41 crossover procedure/
42 double blind procedure/
43 randomized controlled trial/
44 single blind procedure/
45 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44
46 (animal/ or nonhuman/) not human/
47 45 not 46
48 29 and 47
49 (200808* or 200809* or 20081* or 2009* or 2010* or 2011* or 2012*).dd.
50 48 and 49

Web of Science

#24 #23 AND #22
#23 Topic=((random* or blind* or allocat* or assign* or trial* or placebo* or crossover* or cross‐over*))
#22 #21 AND #9
#21 #20 OR #19 OR #18 OR #17 OR #16 OR #15 OR #14 OR #13 OR #12 OR #11
#20 Topic=(hyperhomocyst$in$emi*)
#19 Topic=((cardiovascular near/2 (disease* or event*)))
#18 Topic=(apoplexy)
#17 Topic=((brain near/3 infarct*))
#16 Topic=((cerebr* near/3 (accident* or infarct*)))
#15 Topic=((stroke or strokes))
#14 Topic=(heart attack*)
#13 Topic=(heart infarct*)
#12 Topic=(myocardial infarct*)
#11 Topic=(angina)
#10 Topic=((coronary near/3 disease*))
#9 #8 OR #7 OR #6 OR #5 OR #4 OR #3 OR #2 OR #1
#8 Topic=(pyridoxol*)
#7 Topic=(cyanocobalamin*)
#6 Topic=(cobalamin*)
#5 Topic=(pyridoxin*)
#4 Topic=(((homocystein*) near/3 (low$ or reduc*))) OR Topic=(((homocystin*) near/3 (low or reduc*)))
#3 Topic=(folate*)
#2 Topic=("folic acid")
#1 Topic=("vitamin b")

Appendix 4. Search strategies 2014

CENTRAL

#1 MeSH descriptor Vitamin B Complex explode all trees
#2 (vitamin b)
#3 folic acid
#4 folate*
#5 ((homocystein* or homocystin*) near/3 (low* or reduc*))
#6 (pyridoxin*)
#7 (cobalamin*)
#8 (cyanocobalamin*)
#9 (pyridoxol*)
#10 MeSH descriptor Vitamins, this term only
#11 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10)
#12 MeSH descriptor Cardiovascular Diseases, this term only
#13 MeSH descriptor Myocardial Ischemia explode all trees
#14 MeSH descriptor Brain Ischemia explode all trees
#15 MeSH descriptor Cerebrovascular Disorders, this term only
#16 (coronary near/3 disease*)
#17 (angina)
#18 (myocardial infarct*)
#19 (heart infarct*)
#20 (heart attack*)
#21 (stroke or strokes)
#22 (cerebr* near/3 (accident* or infarct*))
#23 (brain near/3 infarct*)
#24 (apoplexy)
#25 (cardiovascular near/2 (disease* or event*))
#26 MeSH descriptor Hyperhomocysteinemia, this term only
#27 hyperhomocyst?in?emi*
#28 (#12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27)
#29 (#11 AND #28)

MEDLINE

1 exp Vitamin B Complex/
2 vitamin b.tw.
3 folic acid.tw.
4 folate$.tw.
5 ((homocystein$ or homocystin$) adj3 (low$ or reduc$)).tw.
6 pyridoxin$.tw.
7 cobalamin$.tw.
8 cyanocobalamin$.tw.
9 pyridoxol$.tw.
10 Vitamins/
11 or/1‐10
12 Cardiovascular Diseases/
13 exp Myocardial Ischemia/
14 exp Brain Ischemia/
15 Cerebrovascular Disorders/
16 (coronary adj3 disease$).tw.
17 angina.tw.
18 myocardial infarct$.tw.
19 heart infarct$.tw.
20 heart attack$.tw.
21 (stroke or strokes).tw.
22 (cerebr$ adj3 (accident$ or infarct$)).tw.
23 (brain adj3 infarct$).tw.
24 apoplexy.tw.
25 (cardiovascular adj2 (disease$ or event$)).tw.
26 Hyperhomocysteinemia/
27 hyperhomocyst?in?emi$.tw.
28 or/12‐27
29 11 and 28
30 randomized controlled trial.pt.
31 controlled clinical trial.pt.
32 randomized.ab.
33 placebo.ab.
34 drug therapy.fs.
35 randomly.ab.
36 trial.ab.
37 groups.ab.
38 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37
39 exp animals/ not humans.sh. (3663238)
40 38 not 39
41 29 and 40
42 (2012* or 2013* or 2014*).ed.
43 41 and 42

EMBASE

1 exp Vitamin B Complex/
2 vitamin b.tw.
3 folic acid.tw.
4 folate$.tw.
5 ((homocystein$ or homocystin$) adj3 (low$ or reduc$)).tw.
6 pyridoxin$.tw.
7 cobalamin$.tw.
8 cyanocobalamin$.tw.
9 pyridoxol$.tw.
10 Vitamins/
11 or/1‐10
12 Cardiovascular Diseases/
13 exp Myocardial Ischemia/
14 exp Brain Ischemia/
15 Cerebrovascular Disorders/
16 (coronary adj3 disease$).tw.
17 angina.tw.
18 myocardial infarct$.tw.
19 heart infarct$.tw.
20 heart attack$.tw.
21 (stroke or strokes).tw.
22 (cerebr$ adj3 (accident$ or infarct$)).tw.
23 (brain adj3 infarct$).tw.
24 apoplexy.tw.
25 (cardiovascular adj2 (disease$ or event$)).tw.
26 Hyperhomocysteinemia/
27 hyperhomocyst?in?emi$.tw.
28 or/12‐27
29 11 and 28
30 random$.tw.
31 factorial$.tw.
32 crossover$.tw.
33 cross over$.tw.
34 cross‐over$.tw.
35 placebo$.tw.
36 (doubl$ adj blind$).tw.
37 (singl$ adj blind$).tw.
38 assign$.tw.
39 allocat$.tw.
40 volunteer$.tw.
41 crossover procedure/
42 double blind procedure/
43 randomized controlled trial/
44 single blind procedure/
45 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44
46 (animal/ or nonhuman/) not human/
47 45 not 46
48 29 and 47
49 (2012* or 2013* or 2014*).dd.
50 48 and 49

Web of Science

#24 #23 AND #22
#23 Topic=((random* or blind* or allocat* or assign* or trial* or placebo* or crossover* or cross‐over*))
#22 #21 AND #9
#21 #20 OR #19 OR #18 OR #17 OR #16 OR #15 OR #14 OR #13 OR #12 OR #11
#20 Topic=(hyperhomocyst$in$emi*)
#19 Topic=((cardiovascular near/2 (disease* or event*)))
#18 Topic=(apoplexy)
#17 Topic=((brain near/3 infarct*))
#16 Topic=((cerebr* near/3 (accident* or infarct*)))
#15 Topic=((stroke or strokes))
#14 Topic=(heart attack*)
#13 Topic=(heart infarct*)
#12 Topic=(myocardial infarct*)
#11 Topic=(angina)
#10 Topic=((coronary near/3 disease*))
#9 #8 OR #7 OR #6 OR #5 OR #4 OR #3 OR #2 OR #1
#8 Topic=(pyridoxol*)
#7 Topic=(cyanocobalamin*)
#6 Topic=(cobalamin*)
#5 Topic=(pyridoxin*)
#4 Topic=(((homocystein*) near/3 (low$ or reduc*))) OR Topic=(((homocystin*) near/3 (low or reduc*)))
#3 Topic=(folate*)
#2 Topic=("folic acid")
#1 Topic=("vitamin b")

Appendix 5. Definitions of myocardial infarction (MI), stroke, unstable angina and death

Trial

Myocardial infarction

Stroke

Death

BVAIT 2009

Not available

Not available

Not available

HOPE‐2 2006

2 of the following 3 criteria were met: typical symptoms, increased cardiac‐enzyme levels and diagnostic electrocardiographic changes

Focal neurologic deficit lasting more than 24 hours. Computed tomography or magnetic resonance imaging was recommended to identify the type of stroke (ischaemic or haemorrhagic). When these tools were not available, the stroke was classified as of uncertain type

Not available

Cardiovascular causes were unexpected deaths presumed to be due to ischaemic cardiovascular disease and occurring within 24 hours after the onset of symptoms without clinical or postmortem evidence of another cause, deaths from myocardial infarction or stroke within 7 days after the event, deaths associated with cardiovascular interventions within 30 days after cardiovascular surgery or within 7 days after percutaneous interventions, and deaths from congestive heart failure, arrhythmia, pulmonary embolism or ruptured aortic aneurysm. Deaths from uncertain causes were presumed to be due to cardiovascular causes

Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined ‐ a consensus document of the joint European Society of Cardiology/American College of Cardiology Committee for the
redefinition of myocardial infarction. J Am Coll Cardiol 2000;36:959‐69. [Erratum, J Am Coll Cardiol 2001;37:973.]: source not available

NORVIT 2006

See supplementary appendix: www.nejm.org

See supplementary appendix: www.nejm.org

See supplementary appendix: www.nejm.org

See supplementary appendix: www.nejm.org

Definitions are too long to summarise in this table

SEARCH 2010

https://www.ctsu.ox.ac.uk/research/research‐archive/searchs/search‐study‐protocol/view

Accessed: 7 January 2015

https://www.ctsu.ox.ac.uk/research/research‐archive/searchs/search‐study‐protocol/view

Accessed: 7 January 2015

https://www.ctsu.ox.ac.uk/research/research‐archive/searchs/search‐study‐protocol/view

Accessed: 7 January 2015

https://www.ctsu.ox.ac.uk/research/research‐archive/searchs/search‐study‐protocol/view

Accessed: 7 January 2015

Definitions are too long to summarise in this table

SU.FOL.OM3 2010

Myocardial infarction (ICD‐10 (International Classification of Diseases, 10th revision) codes I21.0–I21.9) was defined on the basis of 2 or more of the criteria: typical chest pain, electrocardiographic changes consistent with myocardial infarction and cardiac enzyme increase

An acute cerebral ischaemic event was defined as an ischaemic cerebrovascular accident based on clinical criteria confirmed by computed tomography or magnetic resonance imaging and a Rankin score 3 at inclusion (ICD‐10 codes I63.0–I63.9)

Acute coronary syndrome without myocardial infarction (ICD‐10 codes I20.0–I20.1) was initially defined by the presence of 3 criteria: typical chest pain, electrocardiographic changes consistent with coronary artery disease without myocardial infarction and evidence of coronary artery disease (myocardial infarction, angina with angiographic evidence of stenosis > 50% in one or more coronary arteries, or angina pectoris corroborated by coronary angiography or exercise testing, or coronary angioplasty or coronary artery bypass graft procedure). Suspected acute coronary syndrome without characteristic electrocardiographic evidence of myocardial infarction provided there was angiographic evidence of coronary artery disease

VISP 2004

New ECG changes including Q waves or marked ST‐T changes plus abnormal cardiac enzymes, cardiac symptoms plus abnormal enzymes or symptoms plus hyperacute ECG changes resolving with thrombolysis

Evidence of sudden onset of focal neurologic deficit lasting at least 24 hours accompanied by an increased NIHSS Score in an area that was previously normal. When the sudden onset of symptoms lasting at least 24 hours was not accompanied by an increased NIHSS Score in an area that was previously normal, then recurrent stroke was diagnosed using cranial CT or MRI evidence of new infarction consistent with the clinical presentation

Not available

Not available

WAFACS 2008

According to World Health Organization criteria

A new neurologic deficit of sudden onset that persisted for more than 24 hours or until death within 24 hours

Not available

Death due to cardiovascular disease was confirmed by examinations of autopsy reports, death certificates, medical records and information obtained from the next kin or other family members. Death from any cause was confirmed by the endpoint committee on the basis of a death certificate

WENBIT 2008

According to the Joint European Society of Cardiology/American College of Cardiology Committee. Eur Heart J. 2000;21:1502‐13

According to Cannon CP, Battler A, Brindis RG, Cox JL, Ellis SG, Every NR, et al. A report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee). J Am Coll Cardiol. 2001;38:2114‐30

According to Cannon CP, Battler A, Brindis RG, Cox JL, Ellis SG, Every NR et al. A report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee). J Am Coll Cardiol. 2001; 38:2114‐30

If death occurred within 28 days after the onset of an event, the event was classified as fatal

Homocysteine metabolism (Reproduced with Dr Félix TM's permission from Brustolin 2010)
Figuras y tablas -
Figure 1

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

Study flow diagram for this update
Figuras y tablas -
Figure 2

Study flow diagram for this update

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

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
Figuras y tablas -
Figure 4

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.
Figuras y tablas -
Figure 5

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.
Figuras y tablas -
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.

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.
Figuras y tablas -
Figure 7

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.
Figuras y tablas -
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.

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.
Figuras y tablas -
Figure 9

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.
Figuras y tablas -
Figure 10

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.
Figuras y tablas -
Figure 11

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.
Figuras y tablas -
Analysis 1.1

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.
Figuras y tablas -
Analysis 1.2

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.
Figuras y tablas -
Analysis 1.3

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.
Figuras y tablas -
Analysis 1.4

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).
Figuras y tablas -
Analysis 1.5

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.
Figuras y tablas -
Analysis 2.1

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.
Figuras y tablas -
Analysis 2.2

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.
Figuras y tablas -
Analysis 2.3

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.
Figuras y tablas -
Analysis 2.4

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

Summary of findings for the main comparison. Homocysteine‐lowering interventions (folic acid, vitamin B6 and vitamin B12) compared with placebo or standard care for preventing cardiovascular events

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
Settings: outpatients
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)

Non‐fatal or fatal myocardial infarction
Follow‐up: 1 to 7.3 years

Study population

RR 1.02
(0.95 to 1.1)

43,290
(11 studies)

⊕⊕⊕⊕
high1,2

62 per 1000

64 per 1000
(59 to 69)

Stroke
Follow‐up: 1 to 7.3 years

Study population

RR 0.91
(0.82 to 1.01)

40,815
(9 studies)

⊕⊕⊕⊕
high3,4

52 per 1000

47 per 1000
(43 to 52)

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

Study population

RR 1.01
(0.96 to 1.07)

41,898
(10 studies)

⊕⊕⊕⊕
high5,6

130 per 1000

131 per 1000
(125 to 139)

Cancer
Follow‐up: 3.4 to 7.3 years

Study population

RR 1.06
(0.98 to 1.13)

32,869
(7 studies)

⊕⊕⊕⊕
high7,8

91 per 1000

96 per 1000
(89 to 102)

*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.

1I² = 0%.
243,290 participants with 2986 events.
3I² = 13%.
440,815 participants with 1940 events.
5I² = 6%.
641,898 participants with 5286 events.
7I² = 0%.
832,869 participants with 2892 events.

Figuras y tablas -
Summary of findings for the main comparison. Homocysteine‐lowering interventions (folic acid, vitamin B6 and vitamin B12) compared with placebo or standard care for preventing cardiovascular events
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 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]

Figuras y tablas -
Comparison 1. Homocysteine‐lowering treatment versus other (any comparisons)
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 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]

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