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| VIEW POINT |
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| Year : 2012 | Volume
: 13
| Issue : 2 | Page : 66-68 |
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Vitamin E and Omega-3: What to believe: Observational studies or randomized controlled trials?
Mostafa Yakoot
Green Clinic and Research Centre, Alexandria, Egypt
| Date of Web Publication | 1-Aug-2012 |
Correspondence Address:
Mostafa Yakoot
Consultant Physician, Green Clinic and Research Centre 21121, Alexandria
Egypt
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/1995-705X.99230
 Abstract | | |
The practice of conventional medicine has markedly changed since the introduction of the concept of the evidence-based medicine. Randomized controlled study design and large sample size were the only justifications for level A or B evidence at the summit of what is called the evidence pyramid. A lot of medical interventions that were based on a plethora of basic researches and multiple large real world or observational studies in humans became questioned now by the results of even a single large sized randomized controlled trial (RCT). The conflicting evidences for the value of vitamin E and Omega-3 fatty acids in cardiovascular diseases are famous examples for such perplexity. This article discusses this problem on the basis of scientific, ethical, and statistical critical appraisal. To conclude, in this era of overwhelming flow of data, it should be emphasized in short, fast-to-read articles that it is important to consider not only the level of evidence "as dictated by the study design and sample size" but also the relevance of evidence. Studies tell us about populations but we treat individuals. The type of the studied individuals, the enrollment criteria, the methodology, the dose of the studied drug and all the combined medications in the study should be clearly considered whenever the reported results are to be generalized beyond the specific situation studied. Comparing the effect of an active drug against placebo by giving either one of them to a group already treated with other multiple drugs (optimum medical therapy) could be a misleading indicator for the pure efficacy of the active drug. Many confounding variables such as known "or unknown" drug-drug interactions, sharing mechanisms of action or unexpected adverse drug reactions can afflict only the group randomized to take the active drug. These variables will not affect the control group simply because they add to their optimized multiple drug therapy an inert placebo. Keywords: Observational studies, Omega-3, randomized controlled trials, vitamin E
How to cite this article:
Yakoot M. Vitamin E and Omega-3: What to believe: Observational studies or randomized controlled trials?. Heart Views 2012;13:66-8 |
Since the introduction of the concept of evidence-based medicine, the practice of conventional medicine has markedly changed. Randomized controlled study design and large sample size were the only justifications for level A or B evidence at the summit of what is called the evidence pyramid. A lot of medical interventions that were based on a plethora of basic researches and multiple large real world observational studies in humans became questioned by the results of even a single large sized randomized controlled trial (RCT). This is despite the fact that the decisive reasons for banning many of the "level A" evidence-based registered drugs like Rofecoxib and Rosiglitazone were data from reports of post marketing real-world/observational studies or signals from pharmacovigilance safety reports.
| Vitamin E and Omega-3 and the Conflicting Evidences | |  |
Two of the most famous examples involve vitamin E and Omega-3 fatty acids. There are conflicting evidences for the value of their supplementation in the management of cardiovascular diseases. The role of vitamin E in the prevention of cardiovascular events coming from multiple observational and real world studies done on thousands of volunteers like The Harvard Nurses Health Study and the Health Professional Study [1] became questioned after the release of the disappointing results of large sized RCTs like the HOPE Study. [2] The meta-analysis of randomized controlled studies by Edgar R. Miller et al., also exaggerated this conflict by concluding that vitamin E supplementation may increase all-cause mortality. [3]
Omega-3 was subjected to similar situation after the release of OMEGA study. [4]
Because most of the practicing physicians now adopt the concept of evidence-based medicine, they began to follow the data coming from RCTs as a basis for generalizations to their real life patients even beyond the specific situation studied. They underestimate the data, whatever relevant, if coming from observational studies. Also, the busy cardiologists and internists usually do not find enough time for reading the overwhelming overflow of very lengthy guidelines and full articles; nor do they have the time and skills to analyze or critically appraise the findings. Many cardiologists and general physicians have mistakenly taken the conclusions of the highly advertised HOPE and OMEGA studies to generalize that there are no benefits of giving vitamin E and Omega-3 in all cases. This article discusses this dilemma on the basis of scientific, ethical, and statistical critical appraisal.
| Conflicting Evidence or Conflicting Interventions | | |
How far could the external validity of a study be applied in a setting of a RCT when either the studied drug or the placebo is given as an add-on drug to the optimized multiple-drug therapy in both arms? Do some extraneous baseline factors like the presence of a statin and/or an antiplatelet drug in both arms, such as in the HOPE study, interact with both vitamin E and Placebo in an equal unbiased way? Or is it because they are sharing some of the multi-actions of vitamin E like the antioxidant and antiplatelet effects, they may add net therapeutic benefits to the placebo treated patients more than they will do for vitamin E-treated group?
| The Unequal Drug-Interactions of Baseline Drug Therapy in Both Arms | | |
The answers to these questions were not addressed in the studied parameters. But by using common sense, we can argue that comparing the effect of an active drug with multiple mechanisms of action (like vitamin E and Omega-3 fatty acids) against placebo by giving either one of them to a group already treated with other multiple drugs (optimum medical therapy) could be a misleading indicator for the efficacy of the active drug.
Many confounding variables such as known "or unknown" drug-drug interactions or unexpected adverse drug reactions can afflict only the group randomized to add the active drug. These variables will not affect the control group simply because they add to their optimized multiple drug therapy an inert placebo. As an example, the presence of an optimized antithrombotic therapy in both arms at baseline will provide more antithrombotic benefits to the placebo treated patients than it will do to vitamin E or Omega-3 treated groups. It may even increase the hemorrhagic risk in these groups, as vitamin E given in supplementation doses has its known antiplatelet and vitamin K antagonist activities, whereas Omega-3 is also not neutral in that respect. [5],[6],[7],[8] The same argument may also be applied to other baseline drugs like the statin therapy. For example, most statins can provide antioxidant benefits like vitamin E and can offer more antihyperlipidemic benefits than Omega-3 fatty acids. [9],[10]
| Relevance of Evidence versus Level of Evidence | | |
Are those populations studied in HOPE and OMEGA studies, the type of patients who usually consume vitamin E or Omega-3?
Is the evidence coming from observational studies like the Harvard Nurse Study more relevant for a usual subject who consumes moderate doses of vitamin E for the prevention of coronary artery disease or when he/she cannot take a statin or aspirin?
Usually, the high risk patients like those included in HOPE study are in real life under specialist or secondary medical care and are stuck to their prescriptions with optimized multiple-drug therapy. They usually avoid adding more drugs that can negatively or positively interact with their drugs.
The available relevant evidence for the situation of healthy subjects who do not take an antiplatelet or any other interacting drug therapy and take vitamin E in a dose of about 400 IU, is still to have a significant relative risk reduction with lower coronary artery events or cardiovascular mortality rate than those who do not take vitamin E. [1]
The status for Omega-3 value in cardiovascular disease is less difficult to understand than the case of vitamin E. The comment of Dr. Jochen Senges (University of Heidelberg, Germany) who presented the findings of the OMEGA study at the American College of Cardiology 2009 Scientific Conference is enough to interpret the results. Senges said that the results apply only to the type of particular patients studied who have suffered an acute MI and are receiving optimal medical care (OMT). Omega-3 does not seem to add further benefits to them. Senges added that in other patients without acute MI and without optimized current guideline treatment, Omega-3 might be helpful. It would be incorrect to say that Omega-3 fatty acids are not effective.
| The All-Cause Mortality and the Effect Size in Meta-Analysis | | |
How can we estimate the pure effect size of a drug among so many interacting variables in multinational studies, on all-cause mortality as a very broad and heterogeneous end point?
All-cause mortality is affected not only by age, sex, health status and disease severity, but also geographical, environmental, social, casual, genetic, and many other factors are in play.
In my view, in such multinational studies on high risk patients already on multiple drug therapy, the sub-grouping of all-cause mortality, not only according to cause of death, but also by age group, study center, and the multivariate adjustment for other baseline covariates and confounding risk factors is more ideal to judge for an accurate effect size.
To conclude, in this era of overwhelming flow of data, it should be emphasized in short, fast-to-read articles that it is important to consider not only the level of evidence "as dictated by the study design and sample size" but also the relevance of evidence. Studies tell us about populations while we treat individuals. The type of the studied individuals, the enrollment criteria, the methodology, the dose of the studied drug, and all the combined medications in the study should be clearly considered whenever the reported results are to be generalized beyond the specific situation studied. Comparing the effect of an active drug with multiple mechanisms of action against placebo by giving either one of them to a group already treated with other multiple drugs (optimum medical therapy) could be a misleading indicator for the pure efficacy of the active drug. Many confounding variables such as known "or unknown" drug-drug interactions or unexpected adverse drug reactions can afflict only the group randomized to take the active drug. These variables will not affect the control group simply because they add to their optimized multiple drug therapy an inert placebo.
I presume that encouraging and accepting more publications of high quality real-world pragmatic clinical studies, case series, and real physician experience beside the already prioritized costly sponsored large sized RCTs, will enrich the literature and broaden the transfer of medical knowledge for better treatment of individuals.
| References | | |
| 1. | Jha P, Flather M, Lonn E, Farkouh M, Yusuf S. The antioxidant vitamins and cardiovascular disease. A critical review of epidemiologic and clinical trial data. Ann Intern Med 1995;123:860- 72. 
[PUBMED] |
| 2. | Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:154-60.
[PUBMED] |
| 3. | Miller ER 3 rd , Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46.
|
| 4. | Rauch B, Schiele R, Schneider S, Gohlke H, Diller F, Gottwik M, et al.; Omega-Study Group. Highly purified omega-3 fatty acids for secondary prevention of sudden cardiac death after myocardial infarction-aims and methods of the OMEGA-study. Cardiovasc Drugs Ther 2006;20:365-75.
[PUBMED] |
| 5. | Mousa SA. Antithrombotic effects of naturally derived products on coagulation and platelet function. Methods Mol Biol 2010;663:229-40.
[PUBMED] |
| 6. | Izzo AA, Di Carlo G, Borrelli F, Ernst E. Cardiovascular pharmacotherapy and herbal medicines: The risk of drug interaction. Int J Cardiol 2005;98:1-14.
[PUBMED] |
| 7. | Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm 2000;57:1221-7; quiz 1228-30.
[PUBMED] |
| 8. | Greenblatt DJ, von Moltke LL. Interaction of warfarin with drugs, natural substances, and foods. J Clin Pharmacol 2005;45:127-32.
[PUBMED] |
| 9. | Koksal M, Eren MA, Turan MN, Sabuncu T. The effects of atorvastatin and rosuvastatin on oxidative stress in diabetic patients. Eur J Intern Med 2011;22:249-53.
[PUBMED] |
| 10. | Last AR, Ference JD, Falleroni J. Pharmacologic treatment of hyperlipidemia. Am Fam Physician 2011;84:551-8.
[PUBMED] |
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