Sunday, February 23, 2014

The Diet Heart Hypothesis: Part 3

The Inclusion/Exclusion of Trials 

How is it that that three different meta-analyses arrive at three different conclusions?  Simple, they include/exclude different trials.  Let’s have a look at the meta-analyses and the reasons for including/excluding certain trials (I’ll just discuss the trials where there’s disagreement). 

Hooper
Mozaffarian
Ramsden*
Mine**
Rose Corn Oil Trial
X
X (6)
X
Anti-Coronary Club
Los Angeles Veterans
X
X
X (6+3)
Medical Research Council Trial
X
X
X (6+3)
X
Oslo Diet-Heart Study
X
X
X (6+3)
St Vincent’s Hospital Study
Sydney Diet Heart Study
X
X (6)
X
Finnish Mental Hospital
X
Minnesota Coronary Survey
X
X
X (6)
X
Diet and Reinfarction Trial
X
X
St Thomas Atherosclerosis Regression Study
X
X
X (6+3)
* ‘6’ Refers to a trial where SFA was replaced by omega 6, ‘6+3’ refers to a trial where SFA was replaced by both omega 6 and omega 3
** Hypothetically 

The Rose Corn Oil Trial 

Rose was both randomised and controlled, but Mozaffarian, et al didn’t include it because of “multiple interventions”.  I agree, it did have multiple interventions as the oil groups were encouraged to eat less junk food (fried food, pastry, ice-cream and cakes), but as I pointed out last post if we were to be that strict then unfortunately none of the trials would be eligible.  But they probably didn’t mean that because Mozaffarian, et al included trials that were obviously and deliberately multifactorial (like Oslo and STARS).  They were probably referring to the two oil groups, which isn’t really that relevant because the olive oil group served as a semi-control for corn oil supplementation.  While not exactly the same, Mozaffarian, et al included DART and STARS, which also had ‘multiple interventions’ 

The Los Angeles Veterans Administration Trial 

LA Vets was randomised and well controlled except for the reheating of butter (and consequently vitamin E deficiency) and increase in TFA in the control group, which is why I wouldn’t include it.  However, it was one of the better trials being double blinded and the longest (8 years) and all the meta-analyses included it 

The Oslo Diet Heart Study 

Oslo was randomised, but not well controlled as there were many other dietary differences in favour of the experimental group that were most likely deliberate (more whole foods, LCO3, CLO and vitamin D and less hydrogenated fish oil, refined grains and sugar).  Hooper, et al seems aware of this and the information I got about the diet in Oslo came from Ramsden, et al (so they’re aware of it as well), but they both included it anyway and Ramsden, et al classified it as an omega 3 + omega 6 trial, even though there are many more differences besides the omega 3. 

The Sydney Diet Heart Study 

Sydney was both randomised and controlled.  It was excluded by Mozaffarian, et al because “non-CHD endpoint”, but this wasn’t an issue for Hooper, et al or Ramsden, et al.  The original data did only mention total mortality, but 60 of the 67 (89.6%) deaths were due to CHD.  Easy solution: include it in your analysis for total mortality but not CHD events/mortality 

The Finnish Mental Hospital Study 

FMHS wasn’t randomised or well controlled.  It was excluded by Hooper, et al and because it wasn’t randomised and excluded by Ramsden, et al because it wasn’t randomised and the difference in cardiotoxic medication use between the groups.  Mozaffarian, et al included it and said it was “cluster-randomised”.  Regardless of whether that counts (see Stephan Guyunet’s take), I wouldn’t include it because of all the confounders that on balance were in favour of the experimental group (see the table at the end of this post) 

The Diet and Reinfarction Trial 

DART was randomised and fairly well controlled except for some differences in diet that didn’t seem deliberate (the experimental group increased fruits, vegetables and fish and decreased biscuits and cakes).  Hooper, et al included it, but as a low fat + fat modification trial, rather than a fat modification only trial because the ‘fat advice’ group was also told to reduce their total fat consumption, although the difference between the groups was only 3.2% of total calories.  Ramsden, et al didn’t include it because we don’t know the omega 3 and omega 6 intake in DART, which is understandable since the aim of their meta-analysis was to compare SFA vs. omega 6 trials with SFA vs. omega 6+3 trials 

The St Thomas Atherosclerosis Regression Study 

STARS was randomised, but not well controlled as there were many other dietary differences in favour of the experimental group that were deliberate (weight loss, less trans fat, more LCO3, less baked goods and potentially more whole foods).  Also, the increase in omega 6 in STARS was quite low (difference of 1.6% of total calories).  Like DART, Hooper, et al included it as a low fat + fat modification trial and this time there was a significant difference in fat intake between the groups (27% vs. 37%).  As there were more differences than that, Hooper, et al they flagged it as a trial that wasn’t ‘free from systemic bias in care’ and ‘free from dietary differences other than fat.  Ramsden, et al included it as a omega 6+3 trial even though they acknowledged the small difference in omega 6 intake and were critical of Mozaffarian, et al for including it. 

The Meta-Analyses 

Hooper, et al 

I mostly agree with the study inclusion/exclusion in the Hooper, et al meta-analysis.  I disagree with their inclusion of Oslo because it was so multifactorial (which they were aware of) and deliberately so.  I understand the inclusion of LA Vets, since the trial was high quality (double-blind and long) and differences (vitamin E and TFA) weren’t so obvious.  While DART was intended to be a low fat + fat modification trial (which is why Hooper, et al classified it that way) there was only a slight difference in fat consumption (3.2% of total calories) and actually many of the other trials had an accidental change in fat consumption that was similar in magnitude, but not a big deal 

* I’m also grateful to Hooper, et al as their meta-analysis was where I got all (except one) of the studies for my ‘studies associated with the trial’ section 

Mozaffarian, et al 

I have a few disagreements with the Mozaffarian, et al meta-analysis.  In addition to including Oslo, they also included two other poorly controlled trials that supported the DHH (FMHS and STARS) and FMHS wasn’t randomised, while excluding two unfavourable trials (Rose and Sydney) for poor reasons.  The combination of including three poorly controlled favourable trials while excluding two better controlled unfavourable trials for poor reasons brings up the possibility of bias.  Despite their selection, they still weren’t able to find a reduction in total mortality. 

* The three authors are all epidemiologists at the Harvard School for Public Health.  Are you surprised? 

Ramsden, et al 

The trials included in Ramsden, et al are almost identical to those in Hooper, et al, except the inclusion.  Like Hooper, et al, I can understand why Ramsden, et al didn’t include DART but can’t understand why they included Oslo, since they were aware of all the differences (and informed me of them).  They also included STARS as an omega 6+3 trial even though there are many other differences between the groups.  Ramsden, et al has been a very informative meta-analysis, but I think it misses the mark slightly by dividing the trials up by SFA vs. omega 6 trials and SFA vs. omega 6+3 trials, as many of the ‘SFA vs. omega 6+3 trials’ are very multifactorial and should be considered as such

Sunday, February 16, 2014

The Diet Heart Hypothesis: Part 2

The Difference between Men and Women 

Most of the trials were done in men probably because CVD is thought to be the ‘fat, middle-aged man’s disease’, but CHD is the number one cause of death in women too [1] [2] and yet only two of the trials included women (FMHS and MCS) 

 
Supportive of DHH for CHD Events
Supportive of DHH for CHD Mortality
Supportive of DHH for Total Mortality
FMHS (M/F)
Y/Y
Y/Y*
Y*/-
MCS (M/F)
-/N**
?
-/N**

In these two trials there’s a fairly consistent pattern: men do better than women/women do worse than men (depending on how you look at it).  Since the FMHS had more confounders in favour of the experimental group and the MCS appeared to be well controlled, this suggests that seed oils less likely to confer benefits to women and are more likely to cause harm.  This is particularly unfortunate as women tend to be health conscious and so may end up using more seed oils than men. 

The Difference between CHD Events and Mortality 

The two meta-analyses that supported the DHH both found that replacing SFA with PUFA reduced CHD events, but not total mortality (this minor detail should be quite embarrassing for those who use either meta-analysis as evidence to replace SFA with PUFA) 

 
Supportive of DHH for CHD Events
Supportive of DHH for CHD Mortality
Supportive of DHH for Total Mortality
Hooper (Cochrane)
Y*
RR = 0.82
CI = 0.66 to 1.02
-
RR = 0.92
CI = 0.73 to 1.15
-
RR = 1.02
CI = 0.88 to 1.18
Mozaffarian
(+5% PUFA)
Y
RR = 0.81
CI = 0.70–0.95
Y
RR = 0.80
CI = 0.65–0.98
-
RR = 0.98
CI = 0.89–1.08
* Probably significant with more trials/numbers

Anyway, this particular pattern of results (reduced CHD events, but no difference in either CHD mortality or total mortality) was found in some of the trials, including: ACC (which actually found both increased CHD mortality and total mortality); LA Vets, MRC, FMHS (women only) and MCS (men only and just a 10.5% difference in CHD events).  Two main explanations for this pattern of results could be: 

1) A negative effect of either SFA, TFA or junk food on CHD events but either a less negative, neutral or positive effect on mortality; or a positive effect of PUFA (omega 6, omega 3 or both) on CHD events, but either a less positive, neural or negative effect on mortality.  At least in DART, ‘fish advice’ lowered CHD mortality to a greater extent than CHD events (in fact there were more non-fatal CHD events in the ‘fish advice’ group), suggesting that this pattern of results may not be due to fish or omega 3 [3].  Besides that I’m not sure, but my main guesses would be: (1) the decrease in TFA in the experimental group, which would be expected to reduce blood coagulability and thrombosis, probably preventing minor, non-fatal heart attacks and angina; (2) a difference in post-prandial angina from a meal higher in refined foods and lower in beneficial nutrients (like vitamin E and phytonutrients) 

2) A lack of blinding and bias in the assessment of CHD events and/or CHD mortality.  Bias can occur where the person who assesses CHD events and CHD mortality isn’t blinded and then, whether deliberately or unconsciously, incorrectly assesses CHD events and/or deaths from CHD in favour of a particular group.  In LA vets and MCS the assessors were blinded, but in the ACC, MRC and FMHS they weren’t.  In MRC there was no difference between ‘definite’ CHD events and CHD mortality, but a decrease in ‘probable’ and ‘possible’ CHD events in the experimental group, suggesting the possibility that bias may have influenced the results.  Also, the investigators mentioned that: “one possibility is that the men in the control group themselves may have felt that they were having less active treatment, and might have been psychologically motivated both to complain more and more readily of cardiac symptoms” [4] 

* I’m not saying that replacing SFA with PUFA reduces CHD events because ACC, LA Vets and FMHS had several confounders in favour of the experimental group, the 10.5% decrease in events in MCS was not significant even with 4393 men and there are some issues with the MRC (see above)

PUFA and Non-CVD Morbidity and Mortality 

Mozaffarian, et al and people that use their meta-analysis should be asking: ‘why is it that replacing SFA with PUFA (apparently) reduces CHD events and CHD mortality, but not total mortality*?’  In most of the trials there were only a small number of non-CVD deaths (~0-5), which is to be expected as most of them were secondary prevention trials in middle-aged men.  There were only 5 trials where there were more than 10 deaths from non-CVD causes and probably not a coincidence that 4/5 were primary or primary + secondary prevention and these were the larger trials as well 

Non-CHD Mortality
Experimental Group
Control Group
Anti-Coronary Club
2.21%
1.30%
Los Angeles Veterans
30.4%
24.6%
Finnish Mental Hospital Study (M/F)
28.2/25.7*
25.4/21.1*
Minnesota Coronary Survey (M/F)**
106/80
108/65
Diet and Reinfarction Trial
1.38%
1.58%
* Deaths per 1000 person years
** Minnesota had a high turnover rate and I don’t know what the per 1000 person year figures would be so the figures may not be an accurate representation 

Given the results of Mozaffarian, et al and that they included all of these except the ACC, it shouldn’t be surprising that on average, deaths from non-CHD causes were higher in the experimental group.  The trials generally don’t have good information on the cause of the non-CHD deaths.  However, in the LA Vets there was a near statistical significant increase in cancer in the experimental group (31 vs. 17, p = 0.06), and MCS has a detailed listing on the causes of death, but no clear pattern emerged. 

Chris Masterjohn points out a few things about the LA Vets and potential problems with high PUFA diets in general (highly recommended reading) [5]:
 
  • There isn’t much long term data on very high PUFA diets and no societies eat very high PUFA diets, except the traditional Inuit (a point also made by the LA Vet investigators)
  • High PUFA diets seem to increase the vitamin E requirement and perhaps more so over time with further accumulation of linoleic acid in adipose
  • The increase in cancer deaths and non-CHD mortality in the experimental group only took off after 2 and 7 years respectively
 
All together this suggests that potential harmful effects of high PUFA diets may take at least several years to develop, so we can’t really extrapolate long term health effects from these short term trials. 

Finally, what about non-CHD morbidity and quality of life?  Unfortunately there’s almost no data on this.  In LA Vets there was an increase in gallstone formation in the experimental group (which was correlated with adherence to the experimental diet within the experimental group) [6], but FMHS found no difference in gallstone formation [7].  So, does replacing SFA with PUFA increase gallstones?  I’m not sure, as I don’t much about gallstones, but I do know that the FMHS was less well controlled than the LA Vets.

Monday, February 10, 2014

The Diet Heart Hypothesis: Part 1

The Evidence Against Saturated Fat 

I started this series by looking at the evidence against saturated fat in regards to CVD.  The evidence came from three types of studies 

1.      Observational studies
2.      RCTs examining the effect of SFA on blood lipids
3.      RCTs examining the effect of SFA on CHD events, CHD mortality and total mortality 

Of these only the third can tell us whether replacing SFA with PUFA will reduce CHD events, CHD mortality and total mortality.  The other two shouldn’t be relied upon for dietary guidelines or for establishing causality.  There are instances where things that appear favourable in observational studies and things that lower cholesterol or improve the total:HDL-C ratio have been found to have no effect or an adverse effect in RCTs (see these links) 

There were three meta-analysis done on with trials replacing SFA with PUFA, with inconsistent results.  Two found some benefit and the other found some harm if the PUFA was omega 6.  So I looked at trials in the meta-analyses and two others that weren’t included, the Anti-Coronary Club and the Saint Vincent’s Hospital Study.  Below are the links to the blog posts 


Summary of the Trials 

Below is a table that summarises the details related to the trial and the results of the trial.  I didn’t include all this information in my blog posts.
Legend
Trial Details
Result Details
1) Only looking at the two different oil groups
Y = Yes (replacing SFA with PUFA decreased or end-points)
2) It wasn’t randomised but there was stratification
- = No difference (in cholesterol or end-points between the groups)
3) FL = Free Living, DC = Domiciliary Care, MP = Mental Patients in an institution
N = No (replacing SFA with PUFA increased cholesterol or end-points)
4) Probably no age restriction except over 18 or 21
? = Don’t know as the result wasn’t reported
5) Cross-over design, so only 6 years on each diet
* = Probably significant with a larger sample
6) Turnover rate was a problem
** = Probably significant but researchers didn't say

My Meta-Analysis 

If I were to do a meta-analysis of that looked at trials replacing SFA with PUFA and have high standards, I wouldn’t include any of the trials because none of them did a perfectly simple replacement of SFA with PUFA.  There was always something extra, whether it was restriction of junk food (baked goods usually) and/or trans fats in the experimental group or more obvious things like more fruits, vegetables, fish, etc in the experimental group*. 

The next best controlled trials are those without a multifactorial intervention (deliberate or accidental) besides restriction of junk food and/or trans fat in the experimental group.  These trials are:
  • The Rose Corn Oil Trial
  • The Medical Research Council Trial
  • The Sydney Diet Heart Study
  • The Minnesota Coronary Survey 

If we to look at the results of these trials we get we find:
  • The experimental group reduced cholesterol in all trials
  • In Rose the results were consistently unfavourable for the DHH, but weren’t significant (total mortality came close (0.05 < p < 0.10)), due to the low number of participants (n=80).
  • In MRC there were fewer CHD events but no difference in CHD mortality or total mortality.
  • In Sydney we don’t know how many CHD events there were, but there were significantly more deaths from CHD in the experimental group and almost significantly more deaths from all causes in the experimental group, again probably due to the low number of participants (n=458)
  • In Minnesota we don’t know how many deaths from CHD there were, but there was a small decrease (~10%) in CHD events in the experimental group among men that was not significant and no difference in total mortality among men, although among women there was an increase in both CHD events (31.7%) and total mortality (16.4%) that may be significant, but the researchers didn’t say
Supportive of DHH for CHD Events
Supportive of DHH for CHD Mortality
Supportive of DHH for Total Mortality
Rose
N*
N*
N*
MRC
Y
-
-
SDHS
?
N
N*
MCS
-/N**
?
-/N**

So far these collective results suggest an inconsistency for men regarding CHD events, but likely a minor adverse effect for both CHD mortality and total mortality in men, and nothing but adverse effects in women.

* Except for Minnesota, but in the only paper I had to (the other 3 weren’t even on PubMed) they didn’t discuss the diet in much detail, so I can’t be sure.

The Multifactorial Trials 

Some of the multifactorial trials found either no effect or an inconsistent effect.  While it’s impossible to know the outcome of these trials if these confounding variables weren’t present (would CHD event have been higher in DART, would total mortality have been higher in LA Vets and DART, it’s impossible to know), it suggests the results would have been less favourable for the DHH 

Supportive of DHH for CHD Events
Supportive of DHH for CHD Mortality
Supportive of DHH for Total Mortality
ACC
Y
N**
N**
LA Vets
Y
Y
-
DART
-
?
-

The trials that that more consistently supported the DHH were the most multifactorial.  These trials were Oslo, Finnish and STARS.  The Oslo experimental group had more whole foods, LCO3, CLO and vitamin D and less hydrogenated fish oil, refined grains and sugar.  Finnish had on balance more confounders in favour of the experimental group (see the post).  The STARS experimental group lost weight, had less trans fat, more LCO3, less baked goods and potentially more whole foods.

* The ACC experimental group was instructed to eat more whole plant foods and fish and less junk food and hydrogenated fats.  The LA Vets control group had a vitamin E deficient diet due to reusing the butter for cooking and had hydrogenated fats.  The DART experimental group increased fruits, vegetables and fish and decreased biscuits and cakes. 

Next week I’ll look at differences between men and women, the effect of PUFA on other things, the lower CHD events in the experimental group and a fresh look at the meta-analyses.