Sunday, December 8, 2013

The Los Angeles Veterans Administration Trial

Studies Associated with the Trial

A controlled clinical trial of a diet high in unsaturated fat. Preliminary observations (1962) [1]
A palatable diet high in unsaturated fat (1962) [2] (no access)
Effect of long-term feeding of various fats on whole blood clotting times in men (1964) [3] (no access)
Vitamin E status of humans during prolonged feeding of unsaturated fats (1965) [4] (no access)
Influence of a diet high in unsaturated fat upon composition of arterial tissue and atheromata in man (1965) [5]
Composition of lipids in human serum and adipose tissue during prolonged feeding of a diet high in unsaturated fat (1966) [6]
Adipose tissue linoleic acid as a criterion of adherence to a modified diet (1967) [7]
A Controlled Clinical Trial of a Diet High in Unsaturated Fat in Preventing Complications of Atherosclerosis (1968 [8] (abstract only)
Controlled trial of a diet high in unsaturated fat for prevention of atherosclerotic complications (1968) [9]
Trial of unsaturated-fat diet (1968) [10] (letter to the editor)
Diet and cardiovascular diseases (1969) [11] (letter to the editor)
Prevention of coronary heart disease and other complications of arteriosclerosis by modified diet (1969) [12]
Diet high in unsaturated fat. A controlled clinical trial (1969) [13]
Diet and atherosclerosis (1970) [14] (letter to the editor)
Incidence of cancer in men on a diet high in polyunsaturated fat (1971) [15]
Increased prevalence of cholelithiasis in men ingesting a serum-cholesterol-lowering diet (1973) [16] 

Participants and Diets 

846 male veterans living in a domiciliary unit were randomised to a control group or an experimental group (high PUFA diet).  “Volunteers were accepted into the study regardless of possible pre-existing atherosclerotic complications.”  But were excluded if “they were known to be alcoholic, if they had presented behavior problems, if they were on therapeutic diets, if there were problems of communication, if they had disease likely to result in death within five years or if they were below fifty-five years of age” [1] 

All the subjects ate in a large facility with two dining rooms that served either the control or the experimental diet.  Adherence was tracked by the proportion of meals taken from the correct dining hall.  The meals were ad libitum [1] 

I don’t have access to the detailed data on the diet, which seems to be in this study [2], but it has been briefly described in others: 

“The control diet was a conventional food pattern containing 40 per cent fat calories, mostly of animal origin.” [1] 

“The design of the experimental diet involved substitution of vegetable oils for about two thirds of the animal fat, total fat content being kept about 40 per cent.”.  Eggs were restricted to seven per week.  “Vegetable oils were incorporated into the diet in the form of filled milk, imitation ice cream, "unsaturated" margarine, special frankfurters and filled cheeses. Vegetable oils were used liberally in cooking and baking. Meat fat was minimized by the use of lean cuts, specially trimmed” [1] 

Control
Experimental
Energy (kcal)
2400
2425
Protein (g)
94
95
Fat (g)
108
106
Fat (% of total calories)
40.5
39.3
Linoleic acid (% of fatty acids)
10.0
38.4
Linoleic Acid (% of total calories)
4.0
15.0
PUFA:SFA (ratio)
0.3
1.7
Cholesterol (mg)
721
365
Other Sterols (mg)
150
604
[1] [6] 

Micronutrient intake was not reported except for α-tocopherol (the main form of vitamin E), which was 9.4-fold higher in the experimental group (22.6mg vs. 2.4mg) [5] and only 16.0% of the RDA in the control group [101], indicating a very inadequate intake and a substantial confounding variable in favour of the experimental group.  While vegetable oils tend to be richer sources of vitamin E than animal fats, this is insufficient to explain the 9.4-fold difference between the groups and the very low intake of α-tocopherol in the control group.  An explanation may lie in [4] and while I don't have access Chris Masterjohn does, and he mentioned that: “The researchers took care not to reuse the vegetable oil after cooking but took no such precautions with the butter, resulting in butter that was very deficient in vitamin E”, which makes sense as the nutrient analysis was conducted after the food had been cooked

* 1 mg of α-tocopherol = 1.5 IU of vitamin E

Results

Baseline cholesterol levels were 231 in the experimental group and 232 in the control group.  After 5 years the average cholesterol levels decreased by 20% in the experimental group and 10% in the control group.  Some of the decrease in the control group could be attributed to age. [6] 

In the experimental diet, linoleic acid made up 40% of the total fatty acids.  As a result, among people with good adherence (≥ 80%), the average proportion of linoleic acid in adipose tissue increased from 11% to 32% at 5 years and was projected to increase to ~35%, which seems consistent with proportion of fat from linoleic acid and adherence in this sample (~90%) [6].  At 5 and 6 years there was a correlation between the linoleic acid concentration in adipose tissue and adherence to the experimental diet [7].  They also calculated that the half-time of fatty acid turnover in adipose tissue was 680 days (in other words, 50% of the fatty acids in adipose tissue are turned over after 680 days) [6]

[6]

The primary end-points were sudden death and myocardial infarction (coronary heart disease (CHD) events), and the secondary endpoints included other cardiovascular events.  Both total CHD and total CVD events were lower in the experimental group [9] [12] [13].


Experimental
Control
Definite myocardial infarction by ECG only
9
4
Definite myocardial infarct, overt
33
47
Sudden death
18
27
Definite cerebral infarct
13
25
Ruptured aneurysm
2
5
Amputation for gangrene
7
5
Miscellaneous
3
6
Total coronary heart disease events
60
78
Total cardiovascular events
85
119


CHD mortality and CVD mortality were both lower in the experimental group, with the difference between the groups being significant for CVD mortality (referred to as 'deaths due to atherosclerotic events') [8] [9] [12] [13]


Experimental
Control
Acute myocardial infarct
24
24
Sudden death
18
27
Cerebral infarct
3
9
Amputation
0
3
Ruptured aneurysm
2
5
Intestinal infarct
1
2
Mortality from coronary heart disease
42
51
Mortality from cardiovascular disease
48
70


However, total mortality was very similar, though the actual figure is a  bit ambiguous.  It has been reported as 177 vs. 174 (page 757 [12]) and 174 vs. 178 (page 464 [15]).  Figure 3 in [9] shows it to be higher in the experimental group, while figure 4 in [13] shows it to be lower.  Also, two meta-analyses (Skeaff & Miller, and Hooper, et al) have reported it as 174 vs. 177, but I'm not sure where that comes from and may just be a mistake (switching around 177 vs. 174).

Most of the difference in non-CVD mortality was due to differences in cancer mortality, which was higher in the experimental group (31 vs. 17, p = 0.06) [15].  

Left [9].  Right [13]

Other results include: (1) the average weight in the experimental group increased by 2% whereas the average weight in the control group decreased by 2% [5]; and (2) more gallstones seemed to form in the experimental group than the control group, which was also correlated with adherence to the experimental diet within the experimental group [16] 

Experimental
Control
Autopsies that looked for gallstones in men who a gallbladder
92
95
Gallstones
23
10
Gallbladder removals during the trial
0
4
Percentage (%)
25.0
14.7


Despite the randomisation, there were more heavy smokers in the control group but more moderate smokers in the experimental group.  However, the researchers stratified the incidence of CVD by packs of cigarettes and found that the “uneven distribution of cigarette-smoking habits had no net effect whatsoever on the outcome of the trial” [14]

To finish up, the Los Angeles Veterans Administration Trial was well designed, but the low vitamin E intake in the control group is a major confounding variable in favour of the experimental group and so the results shouldn't be taken at face value.  As total mortality was very similar, the difference in vitamin E intake suggests this is somewhat of an unfavourable trial for replacing SFA with PUFA

Chris Masterjohn has also discussed this trial here and here

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