Here's the abstract of the study, which is called HOPE-TOO (HOPE-The
Ongoing Outcomes = HOPE-TOO . It's an ongoing bit of the HOPE trial
(Heart Outcomes Prevention Evaluation). This is the biggest, longest
prospective blinded and placebo-controlled prospective trial of d-alpha
tocopherol acetate. Basically, vitamin E per se as the d-alpha
tocopherol has been found to do nothing particularly good in heart
disease or diabetes. Worse than that, it increases chance of congestive
heart failure (albeit of a probably mild type). My comments are
appended.

"Effects of Long-term Vitamin E Supplementation on Cardiovascular
Events and Cancer: A Randomized Controlled Trial" The HOPE and HOPE-TOO
Trial Investigators* JAMA, Vol. 293, pp. 1338-47 (March 15, 2005).

ABSTRACT:

Context: Experimental and epidemiological data suggest that Vitamin E
supplementation
may prevent cancer and cardiovascular events. Clinical trials have
generally failed to confirm benefits, possibly due to their relatively
short duration.

Objective: To evaluate whether long-term supplementation with Vitamin E
decreases the
risk of cancer, cancer death, and major cardiovascular events.

Design, Setting, and Patients:  A randomized, double-blind,
placebo-controlled international trial (the initial Heart Outcomes
Prevention Evaluation [HOPE] trial conducted between December 21, 1993
and April 15, 1999) of patients at least 55 years old with vascular
disease or diabetes mellitus was extended (HOPE-The Ongoing Outcomes
[HOPE-TOO]) between April 16, 1999 and May 26, 2003.

Of the initial 267 HOPE centers that had enrolled 9,541 patients, 174
centers participated in the HOPE-TOO trial. Of 7,030 patients enrolled
at these centers, 916 were deceased at the beginning of the extension,
1,382 refused participation, 3,994 continued to take the study
intervention, and 738 agreed to passive follow-up. Median duration of
follow-up was 7.0 years.

Intervention:  Daily dose of natural source Vitamin E (400 IU) [d-alpha
tocopherol acetate] or matching placebo.

Main Outcome Measures:  Primary outcomes included cancer incidence,
cancer deaths, and major cardiovascular events (myocardial infarction,
stroke, and cardiovascular death). Secondary outcomes included heart
failure, unstable angina, and revascularizations.

Results:  Among all HOPE patients, there were no significant
differences in the primary analysis: for cancer incidence, there were
552 patients (11.6%) in the Vitamin E group vs 586 (12.3%) in the
placebo group (relative risk [RR], 0.94; 95% confidence interval [CI],
0.84-1.06; P = .30); for cancer deaths, 156 (3.3%) vs 178 (3.7%),
respectively (RR, 0.88; 95% CI, 0.71-1.09; P = .24); and for major
cardiovascular events, 1022 (21.5%) vs 985 (20.6%), respectively (RR,
1.04; 95% CI, 0.96-1.14; P = .34). Patients in the Vitamin E group had
a higher risk of heart failure (RR, 1.13; 95% CI, 1.01-1.26; P = .03)
and hospitalization for heart failure (RR, 1.21; 95% CI, 1.00-1.47; P =
.045). Similarly, among patients enrolled at the centers participating
in the HOPE-TOO trial, there were no differences in cancer incidence,
cancer deaths, and major cardiovascular events, but higher rates of
heart failure and hospitalizations for heart failure.

Conclusion:  In patients with vascular disease or Diabetes Mellitus,
long-term Vitamin E supplementation does not prevent cancer nor major
cardiovascular events and may increase the risk for heart failure.

==============================

COMMENT by S. Harris:

In the initial shorter duration version of the HOPE trial 3 years ago
(>1800 patients per group), congestive heart failure (CHF) came closest
of any endpoint to being greater in the d-alpha tocopherol acetate 400
IU group, with the RR 1.21 and confidence limits 1.0 - 1.46) p = 0.05.
Hospitalization for CHF didn't come close to significance at p = 0.51.
With larger numbers and longer followup, both these are now significant
in the HOPE-TOO.

The interesting thing is that CHF is usually a consequence of coronary
disease and old MIs. But the number of MIs and other coronary events
really didn't come close to being significantly altered by the vitamin
E in the full study above (which is the only one I have access to,
right now).  The closest of anything was stroke, which had a p of 0.2.
None of the cardiac stuff was much different from RR =1, so it does NOT
look like it was there, but just isn't showing above the noise due to
power problems.

So what's going on?  Of course I have no idea. But this kind of
"congestive heart failure" is not as bad as it sounds to the layman, if
if doesn't increase deaths and doesn't result from any detectable
increase in coronary events. It basically means retention of fluid in
feet or lungs, and hospitalization means there's enough retention in
the lungs to cause problems. We have no way to know if in this study,
the extra cases were due to some global weakening of cardiac function,
or just some odd changes in salt handling and retention (which would of
course be less worrisome). We do know from this and many other studies
that blood pressure and renal function (at least, of the gross
filtration sort) are not affected at all by doses of vitamin E in this
range. So it's a mystery. Still, I'm not going to pretend even this
non-MI-related CHF is okay, although in many practices it would simply
mean an adjustment of diuretic. The bottom line is the only thing
vitamin E does for cardiac patients we can really be sure of, is
something (somewhat) bad.

The main value of these studies is to show that vitamin E as the
d-alpha form, in doses large enough to raise blood levels by 70%, has
NO effect on heart disease progression. Or on diabetes progression. Not
even a hint of it, in a placebo controlled study of many thousands of
people extending many years. I have a whole book (by Wilfred Shute,
M.D. with Harald Taub: _Vitamin E for Ailing and Healthy Hearts_ 1969,
with the 11th paperback printing I have from 1977) claiming that this
very d-alpha tocopherol in similar amounts, is a veritable cure-all for
all cardiac ailments. These claims by the Shute brothers go all the way
back to the 1940's. Every chapter of every health book since the Shutes
started blowing this horn, has had an enormous amount of junk
repetition of all these claims.

Well, these Shute claims appear to be wishful thinking. The real shame
is that it's taken the "medical establishment" half a century to prove
it. And no, there's still no good prospective evidence that vitamin E
prevents cancer in humans, either. (Frankly, I'm a little more hopeful
that selenium will prove out, there. And possibly even vitamin C.)
Vitamin E per se in reasonable and traditional supplemental amounts
(which 400 IU is) certainly doesn't affect onset of diabetes, or
progression of diabetic renal disease. We know that from the HOPE trial
also. I would have wagered a modest amount of money that this wouldn't
be so, from what I know of oxidative mechanisms in diabetes. But I'd
have been wrong. That's why we do these studies.

And no, the HOPE trial goes beyond showing that vitamin E just doesn't
heal the diseased-of-heart (though the Shutes claimed just that). Most
of the HOPE enrollees were not clinically ill, though they did have
coronary disease. If vitamin E even slowed progression of those with
disease, it would have been seen here. It wasn't. The idea that vitamin
E prevents ONSET of coronary disease in totally healthy people who
don't have any at all (if such adults exist in our society), *even
though* it doesn't at all effect progression of disease in people who
already have some, is very far fetched. I think it's grasping at
straws, in fact. I don't believe it, and can't imagine why anybody
would.

Here's the full text of the first phase of the HOPE trial, for the
vitamin E side (as you know, there was another side looking at
preventive effects of giving the ACE inhibitor ramepril).

http://care.diabetesjournals.org/cgi/content/full/25/11/1919

SBH