Vitamins C & E and Atherosclerotic Disease: The Debate Continues

Throughout the past year, I have reported on several studies that looked at the effects of antioxidant vitamins on cardiovascular health.  Unfortunately, as is not uncommon in science, these reports have tended to contradict each other on a regular basis.  So, it is not surprising that a new study, reported in the current issue of the journal Circulation, appears to contradict recent reports that I have reported upon.  The debate basically revolves around the effects, if any, of antioxidant vitamins (and vitamins C & E in particular) on the risk of developing cardiovascular disease.  Two large studies published in the last 6 months have declared that these vitamins have no apparent protective effects on the heart and vascular system.  However, this new study suggests otherwise.

This study, from Denmark and Finland, looked at the effects of vitamin C (250 mg per day) and vitamin E (136 IU per day) on the progression of arterial thickening (atherosclerosis) in the carotid arteries (the arteries that supply the brain with blood) of 520 men and women aged 45 to 69 years.  This “Antioxidant Supplementation in Atherosclerosis Prevention (ASAP)” study first reported its results 3 years into the study.  At that time, the ASAP study showed that daily antioxidant supplementation slowed the progression of carotid arterial thickening in men but not women.  The study is now reporting its results at 6 years.

All of the men and women enrolled in the study had at least mildly elevated serum cholesterol levels (at least 193 mg/dl).  The progression of arterial thickening in these patients was measured with regular ultrasound examinations of the carotid arteries.  The study’s 6-year results found that the rate of carotid artery thickening was slowed down by 33% in men, and by 14% in women (the reduction in the rate of arterial thickening in the women was not statistically significant, however).  Therefore, this study suggests that, at least in men with elevated serum cholesterol levels, daily vitamin C & E supplements may reduce the rate at which critical arteries in the body undergo narrowing due to atherosclerosis.  The results of this study also suggest, at least indirectly, that free radical-initiated damage to the walls of arteries may be more troublesome for men than women, as the antioxidant vitamins are thought to exert their cardiovascular-protective effect by sopping up potentially injurious free radical ions.  It will be interesting, however, to see if longer term data from this study begins to show a significant antioxidant vitamin protective effect in women as well.

Colon Polyp Recurrence after Colonoscopic Polyp Removal

Currently, most authorities recommend that patients with a history of colon polyps detected by colonoscopy undergo repeat colonoscopy every 5 years.  The most common type of true colorectal polyp (adenomatous polyp) is thought to be a precursor to colon cancer.  While not all adenomatous polyps will degenerate into cancers if left alone, there is currently no reliable method to determine which polyps will remain benign and which will develop into cancers.  Therefore, all such polyps are routinely removed when discovered during colonoscopy.

In the current issue of the Archives of Internal Medicine is a study performed by a large HMO that looked at the incidence of recurrent polyps following initial colonoscopic polyp removal.  The study looked at the medical records of 8,865 patients who had undergone colonoscopic removal of a polyp between January 1989 and December 1999.  The patients were followed through September of 2001 for evidence of recurrent colon polyps detected during the course of the study.  Overall, 31% of the study patients were subsequently found to have recurrent polyps in the colon during the study period.  Based upon this data, a statistical model was developed to predict the future incidence of recurrent colon polyps following the detection and removal of a first colorectal polyp.  Based upon this statistical model, it was estimated that 50% of such patients would go on to develop additional polyps within 8 years of the discovery of their first polyp.  These calculations were based upon the total group of study patients, however, and included both patients who obtained regular colonoscopic exams and those who did not.  When the authors then looked at only those patients who obtained regular colonoscopic examinations following their initial diagnosis of a colorectal polyp, the statistical model then suggested that 50 % of patients with an initial colorectal polyp will develop recurrent polyps within 4 years.  These findings suggest a couple of important conclusions.  First, patients who present with one colorectal polyp are at high risk to develop another one, with half of such patients expected to present with new polyps within 4 years of the discovery of the first polyp.  Secondly, many patients with a prior history of colorectal polyps do not return for their regular colonoscopy exams….

Long-term Anticoagulation Reduces the Risk of Recurrent Blood Clots in the Veins

Deep venous thrombosis (DVT) is a condition that occurs when blood clots arise within the deep veins of the leg and pelvis (and, occasionally, in the arms and neck as well).  Complete occlusion of these large veins with blood clots can lead to chronic swelling of the extremities, and to skin breakdown due to high pressure in the remaining small veins of the affected extremity.  A more serious risk is the detachment of a portion of a DVT clot, and the migration of such a clot “embolus” to the lungs.  When pulmonary embolism does occur, 30-50% of patients will die, most of them suddenly.  The standard treatment of acute DVT is to thin the blood for 6 to 12 months using, in most cases, the oral anticoagulant drug Coumadin (also known by its proper name, warfarin sodium).  Such treatment reduces the risk of clot progression in the veins and subsequent embolization, and also improves the body’s ability to recanalize the obstructed veins.  In most cases, the anticoagulation medication is discontinued after 6 to 12 months of treatment.

A new study in the current New England Journal of Medicine looks at the impact of additional long-term anticoagulation on the risk of recurrent DVT in patients who have already completed the traditional duration of treatment with high-dose Coumadin.  The study randomized 508 patients who had already completed their standard Coumadin treatment for DVT to either placebo (sugar pill) or a low-dose regimen of Coumadin.  The patients receiving the low-dose Coumadin were anticoagulated to about two-thirds the level that is usually recommended for the initial treatment of newly diagnosed DVT.  The study was halted prematurely, however, due to a significant difference in the incidence of recurrent DVT between the two study groups.  The study found that low-dose Coumadin reduced the risk of recurrent DVT by 64% when compared to placebo.  The incidence of major hemorrhage was essentially the same between the two groups of patients, suggesting that the risk of Coumadin-related bleeding events was not a problem when used at lower doses.  While there was no significant difference in death rates between the two groups, low-dose chronic Coumadin therapy significantly reduced the risk of recurrent DVT in patients who had previously undergone 6 to 12 months of high-dose Coumadin therapy.  It is very likely that the results of this study will, therefore, result in a reevaluation of the treatment of DVT, and that many physicians will begin to advise their post-DVT patients to remain on chronic low-dose Coumadin therapy after completing a 6 to 12 months course of initial anticoagulation treatment.

Management of Enlarging Thyroid Nodules

 As a surgeon who frequently cares for patients with both benign and malignant thyroid nodules, I found a study in the current issue of the Annals of Internal Medicine to be quite interesting.  One relative indication for thyroid surgery has long been the progressive enlargement of a thyroid nodule despite attempts at suppressing thyroid growth with oral thyroid hormone supplements.  Although most surgeons do not rely solely upon thyroid nodule growth alone as a criterion for thyroidectomy, it is nonetheless a traditional consideration in counseling patients to undergo surgery versus further observation.

This study looked at patients who presented to the Brigham and Women’s Hospital at Harvard University between 1995 and 2000.  All patients had at least one thyroid nodule, and all had undergone fine needle biopsy of their nodules without evidence of thyroid cancer (more about this issue later…).  The patients underwent regular reassessment with physical examination, ultrasound of the thyroid and, in some cases, repeat needle biopsies.  The study found that the thyroid nodules continued to grow over time, with 89% of the nodules increasing in volume by at least 15% over a period of 5 years.  Solid nodules tended to enlarge more consistently than cystic nodules.  A total of 74 of the original 330 thyroid nodules were subjected to repeat needle biopsy during the course of the study, and one of these was malignant.  The authors, therefore, concluded that most thyroids nodules with benign needle biopsies enlarge over time, and that such enlargement is not an indicator of malignancy.

I would agree with the conclusion that most thyroid nodules are both benign and have a tendency to enlarge over time.  However, I would add a couple of caveats.  First, needle biopsies of thyroid are notoriously inaccurate.  A needle biopsy that does not show any evidence of thyroid cancer is, in fact, not a “negative study” at all.  Approximately 75% of all thyroid cancers are of a type (papillary cancer) that can be detected by a needle biopsy.  When a needle biopsy reveals malignant cells consistent with papillary cancer, the diagnosis is almost always accurate.  However, a needle biopsy can miss small papillary cancers, and may therefore not accurately identify such cancers even if they exist (a false negative biopsy).  Moreover, follicular cancer, the second most common type of thyroid cancer (about 25% of cases), cannot be identified with a needle biopsy of the thyroid (although a new test that measures a substance called galactin-3 shows promise in improving the diagnostic accuracy of needle biopsy in diagnosing follicular thyroid cancer). 

Except for a coupe of rare and very aggressive types of thyroid cancer, most thyroid cancers grow very slowly and metastasize late.  The premise of this study is based upon a supposition that a “negative” needle biopsy excludes patients with thyroid cancer.  Although the rather indolent nature of most thyroid cancers may make my point somewhat moot, one can never accurately claim that a thyroid cancer is truly benign because malignant cells were not identified following a needle biopsy.  Finally, although most thyroid cancers grow and spread very slowly, people do still die of thyroid cancers that are diagnosed too late.  The American Cancer Society estimates that in the year 2003, about 22,000 new cases of thyroid cancer will be diagnosed in the United States. Of the new cases, about 16,300 will occur in women, and 5,700 in men.  An estimated 800 women and 600 men will die of thyroid cancer during the year 2003, and most of these deaths will occur in the very young and the very old.

Bottom line, all thyroid nodules need to be carefully evaluated and closely followed by an experienced thyroid physician or surgeon. 


Dr. Robert A. Wascher