See also:

SEARCH study, 2007	TRC3438
[NCT00124072]	download pdf: folic acid, B12 | plasma homocysteine lowering intervention for cardiovascular prevention

Treatments

Studied treatment	folic acid 2mg/d + vitamin B12 1mg/d
Control treatment	placebo
Remarks	factorial design of homocysteine-lowering therapy and simvastatin (80mg/d vs 20mg/d)

Patients

Patients	patients survivors of myocardial infarction
Inclusion criteria	men and women; aged 18 to 80 years; history of myocardial infarction; blood cholesterol levels of at least 135 mg/dL if already taking a statin medication or 174 mg/dL if not
Exclusion criteria	chronic liver, renal, or muscle disease; history of any cancer (except nonmelanoma skin cancer); use of potentially interacting medications
Baseline characteristics	Age (yr) 64.2y  Male sex 83%  BMI NA  diabetes (%) 11%

Method and design

Randomized effectives	6033 / 6031 (studied vs. control)
Design	Factorial plan
Blinding	double blind
Follow-up duration	7 years
Number of centre	88
Geographic area	UK
Hypothesis	Superiority
Primary endpoint	major cardiovascular events

Results

Endpoints and data reported in the trial's publication(s)

Endpoint	Events (%)		Relative Risk	95% CI
	Studied treat.	Control treat.
	6033 / 6033 (100,0%)	6031 / 6031 (100,0%)	1,00	[1,00;1,00]
Nonfatal MI	431 / 6033 (7,1%)	429 / 6031 (7,1%)	1,00	[0,88;1,14]
Coronary revascularization	589 / 6033 (9,8%)	591 / 6031 (9,8%)	1,00	[0,89;1,11]
CHD death	463 / 6033 (7,7%)	423 / 6031 (7,0%)	1,09	[0,96;1,24]
Major coronary event	1229 / 6033 (20,4%)	1185 / 6031 (19,6%)	1,04	[0,97;1,11]
Fatal stroke	59 / 6033 (1,0%)	65 / 6031 (1,1%)	0,91	[0,64;1,29]
Nonfatal stroke	218 / 6033 (3,6%)	221 / 6031 (3,7%)	0,99	[0,82;1,18]
all stroke (fatal and non fatal)	269 / 6033 (4,5%)	265 / 6031 (4,4%)	1,01	[0,86;1,20]
Noncoronary revascularization	178 / 6033 (3,0%)	152 / 6031 (2,5%)	1,17	[0,95;1,45]
Any major vascular event	1537 / 6033 (25,5%)	1493 / 6031 (24,8%)	1,03	[0,97;1,09]

Endpoints used by the meta-analysis and data retained for this trial

Endpoint Studied treat.
n/N Control treat.
n/N Graph RR [95% CI]

All cause death

983 / 6033
951 / 6031
1,03 [0,95;1,12]

Non fatal MI

1229 / 6033
1185 / 6031
1,04 [0,97;1,11]

cardiovascular events

1537 / 6033
1493 / 6031
1,03 [0,97;1,09]

cardiac death

463 / 6033
423 / 6031
1,09 [0,96;1,24]

Cardiovascular death

463 / 6033
423 / 6031
1,09 [0,96;1,24]

stroke (fatal and non fatal)

269 / 6033
265 / 6031
1,01 [0,86;1,20]

Cancer

NA / 6033
NA / 6031
1,07 [0,96;1,19]

Non fatal MI

431 / 6033
429 / 6031
1,00 [0,88;1,14] 0 2 1.0

Relative risks
Endpoint	Events (%)		Relative Risk	95% CI	Endpoint definition in the trial	Ref
	Studied treat.	Control treat.
All cause death	983 / 6033 (16,3%)	951 / 6031 (15,8%)	1,03	[0,95;1,12]		13017
Non fatal MI	1229 / 6033 (20,4%)	1185 / 6031 (19,6%)	1,04	[0,97;1,11]	major coronary events	13017
cardiovascular events	1537 / 6033 (25,5%)	1493 / 6031 (24,8%)	1,03	[0,97;1,09]		0
Non fatal MI	431 / 6033 (7,1%)	429 / 6031 (7,1%)	1,00	[0,88;1,14]		13017
Cardiovascular death	463 / 6033 (7,7%)	423 / 6031 (7,0%)	1,09	[0,96;1,24]		13017
stroke (fatal and non fatal)	269 / 6033 (4,5%)	265 / 6031 (4,4%)	1,01	[0,86;1,20]		13017
Cancer	NA / 6033	NA / 6031	1,07	[0,96;1,19]
cardiac death	463 / 6033 (7,7%)	423 / 6031 (7,0%)	1,09	[0,96;1,24]		13017
The primary endpoint (if exists) appears in blod characters
Reference(s) used for data extraction: 13017: Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, Parish S, Sleight P, Peto R, Collins REffects of Homocysteine-Lowering With Folic Acid Plus Vitamin B12 vs Placebo on Mortality and Major Morbidity in Myocardial Infarction Survivors: A Randomized Trial.JAMA 2010 Jun 23;303:2486-94 0:

Endpoint	studied treat.	control treat.	mean diff

Absolute risk reduction (for a follow-up of 7 years)
Endpoint	Events rate		Absolute risk reduction (ARR)
	Studied treat.	Control treat.
All cause death	16,29%	15,77%	0,53%
Non fatal MI	20,37%	19,65%	0,72%
cardiovascular events	25,48%	24,76%	0,72%
Non fatal MI	7,14%	7,11%	0,03%
Cardiovascular death	7,67%	7,01%	0,66%
stroke (fatal and non fatal)	4,46%	4,39%	0,06%
cardiac death	7,67%	7,01%	0,66%

Meta-analysis of all similar trials:

plasma homocysteine lowering intervention in cardiovascular prevention for all type of patients

Reference(s)

TrialResults-center ID	TRC3438
Trials register #	NCT00124072
Study web site link	http://www.ctsu.ox.ac.uk/projects/search.shtml

• Bowman L, Armitage J, Bulbulia R, Parish S, Collins R. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors.. Am Heart J 2007 Nov;154:815-23, 823.e1-6
  Pubmed | Hubmed | Fulltext
• MacMahon M, Kirkpatrick C, Cummings CE, Clayton A, Robinson PJ, Tomiak RH, Liu M, Kush D, Tobert J. A pilot study with simvastatin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH).. Nutr Metab Cardiovasc Dis 2000 Aug;10:195-203
  Pubmed | Hubmed | Fulltext
• Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, Parish S, Sleight P, Peto R, Collins R. Effects of Homocysteine-Lowering With Folic Acid Plus Vitamin B12 vs Placebo on Mortality and Major Morbidity in Myocardial Infarction Survivors: A Randomized Trial.. JAMA 2010 Jun 23;303:2486-94 - 10.1001/jama.2010.840
  Pubmed | Hubmed | Fulltext
• Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, Parish S, Sleight P, Peto R, Collins R. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial.. JAMA 2010;303:2486-94 - 10.1001/jama.2010.840
  Pubmed | Hubmed | Fulltext

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