Vitamin E supplementation and cardiovascular events in high risk patients 

Authors The Heart Outcomes Prevention Evaluation (HOPE) study investigators.
Source New England Journal of Medicine 342:154-60. January 20, 2000. 
Institutions Multi-institutional and international.
Support Medical Research Council of Canada, Natural Source Vitamin E Association, Negma, Hoechst- Marion Roussel, AstraZeneca, King Pharmaceuticals,  and the Heart and Stroke Foundation of Ontario.

 

Background

Experimental and observational studies have indicated a role for the antioxidant vitamin E in the prevention of atherosclerosis and cardiovascular events.  However, the few randomized trials conducted so far have not been unequivocally positive and have suffered from a number of limitations.  This study examined the effect of vitamin E supplementation on cardiovascular events in high risk patients.  It was conducted as part of the HOPE trial, which also looked at the benefit of an ACE inhibitor in patients at risk for cardiovascular events.

 

Methods

Patients

Eligible:  Patients at least 55 years old with a history of: any of the following:

  • coronary disease
  • stroke
  • peripheral vascular disease
  • diabetes plus another cardiovascular risk factor (hypertension, elevated cholesterol, low HDL, cigarette smoking or microalbuminuria)

Exclusion criteria:  

  • congestive heart failure or a documented ejection fraction less than 40%
  • patients taking an ACEI or vitamin E
  • MI or stroke within the previous 4 weeks
  • uncontrolled hypertension
  • overt nephropathy


Intervention

Patients were randomized to either 400 IU of vitamin E from natural sources or to placebo (in addition to being randomized to ramipril or placebo, as the other part of the HOPE study).

Follow-up

Follow-up visits occurred at one month, 6 months and every 6 months thereafter, with follow-up planned for 5 years.

Analysis

The primary outcome was a composite of cardiovascular death, MI or stroke; each of these outcomes was also analyzed separately.  Secondary outcomes were all-cause mortality, hospitalization for CHF or unstable angina, revascularization and the occurrence of diabetic complications.  A number of other cardiovascular complications were also recorded.

Results

Patients

Of 10,576 patients who enrolled in the study and participated in the run-in phase for the ACEI part of the study, 1,035 were excluded because of withdrawal of consent, noncompliance, electrolyte abnormalities or side-effects.  Of the 9,541 remaining patients, 4,761 were assigned to receive vitamin E and 4,780 were assigned to placebo.

Baseline characteristics included (my approximate average of both groups):

  • Male sex: 73%; age: 66 years
  • BP: 139/79; BMI: 28
  • History of coronary disease: 80% (prior MI 53%; CABG 26%; history of angina 56%)
  • History of stroke or TIA: 11%
  • Peripheral vascular disease: 43%
  • Hypertension: 47%; diabetes: 38%; hypercholesterolemia: 66%; current smokers: 14%
  • Currently on beta-blockers: 39%; aspirin: 76%; lipid agents: 29%; calcium blockers: 47%

Subsequent chart review of randomized patients revealed that 54% had had their LV function determined; it was less than 40% (an exclusion criterion) in about 8% of patients.


Length of treatment and compliance

Patients were recruited between December, 1993 and June, 1995.  Length of treatment and follow-up was to be 5 years, but the trial was halted approximately one year early (April, 1999) because of interim analyses showing clear efficacy for the ACE inhibitor.  The mean length of follow-up was 4.5 years.

At the end of the study, 89.2% of patients assigned to vitamin E were taking it, and 3.4% of patients assigned to placebo were taking vitamin E.

Main outcomes

There was no significant difference in the primary endpoints between patients receiving vitamin E or placebo.

 
  Vitamin E Placebo Relative risk p-value
Death from cardiovascular causes 7.2% 6.9% 1.05 NS (0.54)
Death from non-cardiovascular causes 4.0% 4.4%    
Death from any cause 11.2% 11.2% 1.0 NS (0.99)
Myocardial infarction 11.2% 11.0% 1.02 NS (0.74)
Stroke 4.4% 3.8% 1.17 NS (0.13)
Composite endpoint: MI, stroke or cardiovascular death 16.2% 15.5% 1.05 NS (0.33)

These results were not different in patients receiving or not receiving the ACE inhibitor.

The incidence of the secondary endpoints also did not differ between patients receiving vitamin E and placebo.

 

Subgroup analyses and adverse effects

These results were not heterogeneous across various subgroups, including age, sex, cardiovascular disease, medications, diabetes or smoking status.

There was no difference between the groups in the incidence of adverse effects or drug discontinuation (data not given).

Author's discussion

According to the authors, this study did not demonstrate any significant reduction in the incidence of cardiovascular events by the administration of 400 units of vitamin E for four to six years.

They describe and comment on the results of four randomized clinical trials of vitamin E:

  • A chinese trial that randomized patients to a combination of vitamin E, beta carotene and selenium or placebo.  This trial showed a 9 percent decrease in all-cause mortality, but no decrease in cardiovascular events.  The effect of vitamin E could not be separated out, and the nutritional status of the population is different from that in the population studied here.
  • The ABC trial (Alpha- Tocopherol, Beta Carotene Cancer Prevention) studied over 29,000 male smokers between the ages of 50 and 70. Fifty mg of vitamin E daily showed no significant beneficial effect on cardiovascular events.
  • The Cambridge Heart Antioxidant Study assigned patients with coronary disease to vitamin E (400 IU or 800 IU) or placebo.  There was a significant decrease in the number of nonfatal MI's, but not in cardiovascular mortality.  The numbers were small, the effects were seen too quickly to be easily attributable to the antioxidant properties of vitamin E and there were imbalances in the study groups.
  • An Italian study randomized 11,000 post-MI patients to 300 IU vitamin E or placebo; there was no statistically significant effect on cardiovascular events.

The authors note that their results could be due to inadequate length of follow-up, but observational studies suggest that effects should be apparent within 2 years.  Furthermore, in a nested substudy of this trial they are now examining a surrogate marker for atherosclerosis which would be expected to show earlier results: the carotid artery intima-media thickness.

Another possible explanation for the negative results could be a need for vitamin E to be combined with other antioxidants; other trials looking at this hypothesis are in progress. 

 

Comment

This randomized trial of 400 IU of vitamin E vs. placebo failed to show any decrease in cardiovascular events after 4.5 years of follow-up.  This, despite the fact that multiple observational trials had suggested a beneficial effect.  One of the areas where observational trials are most likely to be influenced by bias is when analyzing data that reflect "healthy" behaviors.  Since healthy diets and vitamin supplementation are strongly associated with other beneficial lifestyle aspects, it is extremely difficult to avoid the intruduction of bias.

The trial was halted early because of a significant benefit in the ACE inhibitor portion of the study.  This could have led to an inadequate length of follow-up to detect a beneficial effect of vitamin E.  But, as the authors point out, a beneficial effect of vitamin E would have been expected before the 4.5 years of follow-up that were available here, so the early termination is unlikely to have played a major role in the negative result.

This study does not disprove the role of vitamin E in cancer prevention (still being followed in some of the patients enrolled in this trial), does not necessarily disprove a potential role when combined with other antioxidants, and certainly doesn't negate the potential beneficial role of a diet that is naturally high in vitamin E.  It does, however, call into question the role of vitamin E supplements alone for the prevention of cardiovascular events.

 

July 4, 2000

References

References related to this article from the NLM's PubMed database. 
 

Reader Comments

July 5, 2000
From: Samim Chalabi Çelebi [samim.celebi@fornet.net.tr]

Dear Dr Jacobson,

Thank you for always interesting cases. It is important to stress that a single cause for vascular disease and events does not apply or else it would have been sorted out earlier.

First, we need to look at the stress factor involved in these patients and this might be difficult.

Second, we need to know in younger generations that are at high risk whether vit e is preventive before disease starts, like 20 - 30 years of age, as probably prevention is much more effective than treatment in those patients.

Third, we hope that genetics will give us insight on who wil benefit and who willl not.

thank you, samim

 

Factors like stress and genetics, although important in the pathogenesis of vascular disease, were presumably evenly distributed between the patients assigned to vitamin E and placebo, and thus should not invalidate the results presented here.

Since the study was limited to just a few years, you are right that we can not be sure that earlier and longer treatment would not be effective.  The authors partially address this question in the article.

In general, I agree with you that once there is better understanding of a disease process, it is easier to target smaller groups who are much more likely to benefit from an intervention on that process.  -- mj

July 5, 2000
From: Enrique S. Corvalan, MD [corvalan@U.Arizona.EDU]

This study deals entirely with "secondary prevention" of CV events in a fairly sick population. I would be interested to know same outcomes for a "primary prevention" point of view. Example: patients without CV proven disease but with hyperlipidemia, HTN, Diabetes, etc.

Enrique S. Corvalán, MD, ABFP, FAAFP
Assistant Professor Clinical 
Family & Community Medicine

 

It is true that these results apply to a very specific population, those at highest risk.  However, this is precisely the population in which prevention should be the easiest to demonstrate.  If it can't be shown in this population, then it's unlikely to be demonstrable in a population at lower risk.

Unless, of course, you postulate that these patients are at such high risk that a  beneficial intervention such as vitamin E is powerless to help them, or that lower-risk patients are somehow susceptible to vitamin E's effects in a way that high-risk patients aren't.  Not impossible, but unlikely, in my opinion.  --mj

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