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Reduce Risk of Breast Cancer

Posted by medconsumers on May 1, 2006

Drugs to Reduce Breast Cancer Risk: Is It Worth It?

Initial results from a government-sponsored study indicate that the osteoporosis drug raloxifene (brand name: Evista) may protect against breast cancer. The study compared it against an older anti-breast cancer drug, tamoxifen (brand name: Nolvadex), and found both are equally good at reducing the chances of developing breast cancer. Some media reports of this study were overly enthusiastic about its finding.

The study is yet to be published and therefore has not been peer-reviewed. If the results hold up, Eli Lilly, maker of raloxifene, will be able to apply to the FDA for permission to promote raloxifene as a breast cancer preventive. Expect an overheated advertising campaign by Lilly touting raloxifene as a “two-for”—a drug that will save women from osteoporosis AND breast cancer.

Raloxifene has been on the market since 1997. It is good at increasing bone density; completely ineffective at reducing the most serious type of fracture (hip); and minimally effective in reducing spinal fractures. Spinal fractures can cause pain and a dowager’s hump in advanced age, but many are entirely symptomless. Tamoxifen has been on the market since 1972. First as an adjunctive treatment for breast cancer and more recently (1998) as a preventive drug for healthy but high-risk women. It never took off for the latter purpose because, according to one report, many doctors were uneasy about prescribing a cancer drug to healthy women every day for five years.

Both raloxifene and tamoxifen are what is called selective estrogen receptor modulators, or SERMs, which means that they protect the breast from estrogen’s cancer-causing potential but preserve estrogen’s protective effect on the bones. This is why SERMS were initially promoted as designer estrogens.

The National Cancer Institute sponsored the new study that compared the two drugs called the STAR trial, short for Study of Tamoxifen and Raloxifene, and the initial results were posted last month on its Web site (www.cancer.gov see initial results STAR). The STAR trial included postmenopausal women at high risk for breast cancer who had been randomly assigned to take one or the other drug. The NCI hailed both drugs as having reduced the incidence of breast cancer by 50%, which was uncritically picked up by most of the media.

Here’s what the NCI should have explained: Of the 9,700-plus women in each drug group, about 165 got breast cancer. This translates to 1.7%; whereas, 3.4% would be expected to develop breast cancer had they not taken a drug. (Hence the 50% reduction in breast cancer incidence.) Another way of saying the same thing is: 98.3% of high-risk women will not get cancer if they take raloxifene or tamoxifen; whereas, if they take no drug, 96.6% of women will not get cancer. Obviously, much more research is needed to determine who is at high risk for breast cancer.

If you are thinking of taking raloxifene every day for five years, consider the following:

It is premature to call raloxifene and tamoxifen preventive drugs. The STAR lasted only four years and breast cancer can take from 12 to 17 years to develop. Therefore, it is not known whether these drugs prevent breast cancer or merely delay its onset. The Tamoxifen Breast Cancer Prevention Trial lasted nearly five years.

The media reports of STAR emphasized fewer adverse reactions for raloxifene. However the 29% fewer blood clots and 36% fewer uterine cancers are not considered to be statistically significant because these conditions are rare. (Findings could have occurred by chance.) However, the finding of fewer cataracts in the raloxifene users is statistically significant. There were fewer cases of noninvasive breast cancer (e.g., ductal carcinoma in site, which does not always become life-threatening if left undetected.) in the women taking tamoxifen. [Note: When the STAR results were reported at a June meeting of the American Society of Clinical Oncology and published simultaneously online in the Journal of the American Medical Association, there was no overall difference between the two drugs in the study participants’ self-reported side effects—with some exceptions. Hot flashes, vaginal bleeding, bladder control problems were more common in women on tamoxifen. And pain during sexual intercourse and joint pain were more common in those on raloxifene.]

Raloxifene’s spinal fracture reduction benefit is small. Three-year results of a major trial showed spinal fractures in 10.1% of the women on placebos; in 6.6% of women on 60-mg/daily of raloxifene; and in 5.4% for women on 120 mg/daily of raloxifene.

Less is known about the long-term effects of raloxifene than is known about tamoxifen. It took more than 25 years of tamoxifen use before a rare life-threatening adverse effect (endometrial sarcoma) became apparent.

Maryann Napoli, Center for Medical Consumers ©May 2006

For another perspective on this study, see Breast Cancer Action’s Newsletter

http://www.bcaction.org/Pages/SearchablePages/2006Newsletters/Newsletter092A.html

Posted in Cancer, Women's Health | Tagged: , , , | Comments Off

Women’s Health Advice Falls Short

Posted by medconsumers on March 1, 2006

Prevention Advice to Women Doesn’t Hold Up

This is not the first time we’re seen medical dogma upended. Remember breast self-examination? It was proven to have no life-saving benefit and an increased risk of unnecessary breast biopsies. Now it is calcium supplements and a low-fat diet that will not save your life.

February 2006 was a banner month for disproving medical dogma. First, the public learned that the low-fat diet does not prevent heart disease. The next week, another study found that calcium does not protect against fractures or colon cancer. And in between, yet another study provided the surprising news that estrogen might lower the risk of heart disease in some women. (This last one actually reconstituted a previously disproved medical belief. For over ten years, women had been told that estrogen will save them from heart disease, but a major clinical trial was stopped early several years ago when it found that this hormone caused heart-related problems.) In each case, the findings were strongly contested.

Women’s Health Initiative

All these newsworthy announcements came from the same landmark clinical trial called the Women’s Health Initiative (WHI), an $18 million government-funded project, which involves thousands of healthy women over age 50. It is designed to test the prevailing health advice about how to prevent the chief causes of death and disability in older women.

Medical research is constantly evolving and we should expect health advice to change as more studies are published. But how is it that so many recommendations based on uncertain evidence can become orthodoxy? Recall how women were made to feel negligent by their doctors for not doing breast self-exams. A similar guilt was laid on those who refused to take postmenopausal hormones or were doubtful about high-dose calcium.

Surrogate Endpoints

Physician acceptance of the preventive measures was nearly universal, though they were based on a less reliable type of study called population, or observational studies. In this type of study, for example, the women who chose to take estrogen (as opposed to being randomly assigned to take it in a clinical trial) tended to have lower rates of heart disease. A closer look at these less reliable studies showed that women in the higher income brackets were more likely to take estrogen, and a high income is known to be associated with better health and a longer life.

Often, health recommendations are based on what researchers call surrogate endpoints—plus a heavy dose of assumptions. Estrogen lowers cholesterol in women; therefore it must save them from heart disease. Calcium improves bone density; therefore it must cut the risk of hip fracture. Long-term  trials that follow participants until they have a heart attack or a hip fracture are expensive and take many years to produce answers, which is why so much health advice is based on surrogate endpoints.

The WHI is a massive research effort that involves multiple clinical trials. As researchers continue to sift through the data generated by the WHI, they will be publishing results for years to come. What follows is a summary of the evidence (or gaps in the research) that led the WHI to study the low-fat diet, high-dose calcium, and estrogen in younger women; the doubts that long surrounded each preventive measure; and the questions that remain unanswered.

LOW-FAT DIET AND HEART DISEASE

The supporting evidence:

No long-term trial had ever been conducted to support the idea that a low-fat diet (below 20% of total calories) reduces the risk of heart attack in healthy older people. While the WHI was still underway, a 2001 Cochrane review on this topic was published in the British medical journal, BMJ. Lee Hooper, PhD, and colleagues assessed all clinical trials in which healthy older men and women had been randomly assigned to continue on their normal diet or go on a low-fat or a reduced-fat diet.

This review exposed the difficulty in finding definitive answers as heart disease takes years to develop and few of the trials lasted more than six months. Results were predictably unimpressive: There was no reduction in heart attacks or cardiac deaths, but the few trials that lasted two years hinted at a lower risk of heart  disease.

Flaws in the WHI:

The most valid criticism of the WHI/diet trial centers on the fact that it made no distinctions in the types of fat, as in: olive oil is good; trans-fatty acids (partially hydrogenated vegetable oils) are bad. Participants were simply instructed to keep their total fat intake below 20%. Because the WHI was designed 15 years ago, it reflects the general thinking among nutrition scientists at the time, said nutrition scientist Sharon Akabas, PhD, in a telephone interview. “As recently as 12 to 15 years ago, you still had people [in the nutrition field] who thought trans-fatty acids were OK and omega-3 fatty acids were seen as fringe—olive oil and other monosaturated oils were thought to be neutral.”

The Mediterranean-type diet is favored by many nutritionists today and that is a glaring omission of the WHI, according to Dr. Akabas, who is associate director of education at the Institute of Human Nutrition, Columbia University in New York City. “If I could design the WHI now, I would have had a group whose fat intake was 40% of calories with a significant contribution from olive oil. The Mediterranean diet also puts more emphasis on omega-3 fatty acids; it is high in plant food; low in animal foods; has more whole food; and less processed foods,” she said, adding that there is more to healthful living than dietary choices. Referring to the numerous population studies that showed the Mediterranean diet to be one of the most healthful in the world, Dr. Akabas continued, “People eating the Mediterranean diet at the time of these studies were taking a nap in the afternoon, they didn’t snack all day; they were physically active. And they are on the diet by choice, as opposed to have it imposed on them during a study.”

Doubters Have Reason to Remain Doubtful:

Even the highly motivated women who volunteered for the WHI could not get their fat intake under 20% of calories. (Many critics of the WHI saw this as a sign that a low-fat diet is impossible for Americans.) The best the WHI participants could do was 24% in the first year and 29% in the subsequent years. Since that narrowed the difference between them and the other women who had been assigned to remain on their usual diet, the WHI results were seen by some critics as not proving anything one way or another about the value of the low-fat diet.

The most steadfast proponent of the low-fat diet is Dean Ornish, MD, president of Preventive Medicine Research Institute and clinical professor of medicine at the University of California, San Francisco. The author of several books about reversing heart disease, Dr. Ornish has also co-authored a study that showed regression of severe coronary atherosclerosis after only one year, without the use of cholesterol-lowering drugs. In addition to a low-fat vegetarian diet, the study participants took part in a program of comprehensive lifestyle changes that included smoking cessation, stress management training, and moderate exercise. As yet, Dr. Ornish has not published a clinical trial that proves his program results in lower rates of heart attack or cardiac death.

Other Potential Benefits to Low-Fat Diet

The WHI produced a hint that even small reductions in dietary fat might reduce the risk of developing breast cancer. There was a 9% reduced rate of breast cancer in the women who attempted a low-fat diet, but this was not regarded as statistically significant, though it came close. Dr. Jacques Rossouw, the project officer for the WHI has stated that this finding might have become statistically significant had the trial lasted longer.

CALCIUM AND HIP FRACTURES

Supporting Evidence:

The body needs calcium for strong teeth and bones. That’s a fact. A controversy, however, surrounds the question whether anyone (including children) has to get it from milk or other dairy foods. It was also unclear whether massive increases in calcium intake in middle  age will make any difference in fracture reduction.

Many population or observational studies show an increase in calcium intake in middle age improves bone density, but others show that women with high intake of calcium from diet or supplements actually have higher rates of fractures. Until, the WHI published its results last month, no well-designed clinical trial followed women long enough to prove increased calcium intake in middle age will reduce the rate of hip fractures.

The WHI Findings:

The WHI/calcium plus vitamin D trial involved 36,282 women. The hip fracture rate in those taking calcium plus vitamin D was the same as that of the women taking inactive placebos. One benefit shown in the calcium/vitamin D3 group was a 1% increase in bone density at the hip. Another is a slightly lower risk of hip fracture in one subgroup—women over the age of 60 years at the start of the trial.

Only 70% of the women in the calcium/vitamin D group took their assigned supplements regularly. When the investigators looked solely at this group, they found that these women had 29% fewer hip fractures than those taking placebo. In other words, there were 10 compared to 14 hip fractures per 10,000 women each year.

Furthermore, the supplements did not prevent colon cancer as originally thought, but they slightly raised the risk of developing kidney stones. There were an additional five cases of kidney stones per 10,000 women per year among those on supplements.

Doubts That Remain:

Since the WHI was planned, researchers have begun to view the recommended dose of vitamin D3 (400 international units) as inadequate and the recommended dose of calcium (1200 milligrams) as excessive. The WHI chose to use a daily dose of 1,000 milligrams of calcium and 400 international units of vitamin D3 (cholecalciferol). Last year, an analysis of all clinical trials that looked at the relationship between fractures and vitamin D was published in the Journal of the American Medical Association. It concluded: “Oral vitamin D supplementation between 700 to 800 IU a day appears to reduce the risk of hip and any non-spinal fractures in ambulatory or institutionalized elderly persons. An oral vitamin D dose of 400 IU/day is not sufficient for fracture prevention.”

Doubters Proven Correct (so far):

The two high-profile doubters about the relevance of calcium intake to hip fracture are Walter Willett, MD, Harvard School of Public Health, and T. Colin Campbell, PhD, professor emeritus of nutritional biochemistry at Cornell, who have, respectively, conducted numerous studies on the topic. Both argue that there is too much focus on calcium and too little focus on exercise and vitamin D. Both cite the excessive protein intake in the American diet, primarily from meat as a probable cause of hip fracture (though this was not factored into the WHI).

For the last 25 years, Dr. Willett has been one of the principle investigators of the Nurses’ Health Study, which has spawned scores of nutrition and health related studies including one that found the highest rates of hip fracture among women with the highest calcium intake.

Dr. Campbell directed the Cornell-China-Oxford Project, the most comprehensive project on diet and disease ever conducted. He has observed: “Most of the world’s peoples do not consume cow’s milk, and yet most of the world does not experience the high rates of osteoporosis found in the West. In Asian countries, for example, where consumption of dairy foods is low (and where women tend to be thin and small-boned, universally accepted risk factors for osteoporosis), fracture rates are much lower than they are in the United States and in Scandinavian countries, where consumption of dairy products is considerably higher.”

ESTROGEN AND HEART DISEASE

New Evidence for Women Without a Uterus:

One component of the WHI was designed to test several assumptions about the health effects of hormone therapy by comparing it to a placebo. This trial made international headlines in 2002 because it had to be stopped early. There was a higher rate of heart disease, breast cancer, blood clots, and stroke among the participants who had been taking combination hormones, estrogen and progestin (the latter hormone is necessary only for women with an intact uterus due to estrogen’s ability to increase the risk of uterine cancer). Though the hormone combination was also associated with decreased risk of colon cancer and hip fracture, it is no longer universally recommended as a preventive measure because the risks clearly outweigh the benefits.

Another “arm” of the WHI/hormone study continued to follow the 10,739 participants who had undergone a hysterectomy. All had been randomly assigned to take daily doses of estrogen (0.625 milligrams) or a placebo. Their mean age at entry into the WHI was 63 years. In February 2003, this arm of the WHI was also stopped early due to a higher stroke rate among women on estrogen.

The WHI Findings:

A study that looked at the heart-related WHI findings for the hysterectomy group was published last month in the Archives of Internal Medicine. After about seven years, the rate of heart attack and cardiac death was exactly the same for both the estrogen and the placebo groups. But there was “a suggestion” of a lower heart disease risk only among the women who had started taking estrogen while in their fifties. There was no suggestion of benefit in women who were 60 years or older when they started taking estrogen. Stroke was not taken into account in this particular study.

Doubts that Remain:

Whenever researchers use the word suggestion to describe their results, as in “a suggestion of lower heart disease risk,” they are saying that the findings aren’t clearly established. Despite the breathless headlines that went out across the country heralding the results of this study (“Estrogen May Help Heart”), they could be due to chance, which is how the WHI Web site (see below) describes them. A co-author of this study, quoted frequently in the media, saw the lack of an increased risk of heart disease as reassuring to women who want to take hormones on a short-term basis to alleviate hot flashes.

For More Information:

The WHI is a 15-year project that includes 161,000 women. It is paid for by taxpayer money, and as such, the WHI has been entirely open—via its Web site (www.whi.org)—about its findings both good and bad. The WHI has two major components: a randomized clinical trial (RCT) and an observational study. The RCT section is divided into three additional components: hormones, dietary modification and calcium/vitamin D.

Maryann Napoli, Center for Medical Consumers ©
March 2006

Posted in Alternative Medicine, Cancer, Heart, Women's Health | Tagged: , , , | Comments Off

Popular Supplements Studied

Posted by medconsumers on March 1, 2006

Melatonin for sleep problems, glucosamine plus chondroitin for knee arthritis, and saw palmetto for symptoms of an enlarged prostate. Each one of these remedies has recently been subjected to a clinical trial that compared it against a placebo, or inactive pill. Results were disappointing.

All these remedies were classified as nutritional or dietary supplements that can be purchased over the counter, which is a large part of their appeal. So is the fact that these supplements are widely viewed as safer, more effective alternatives to prescription drugs. In all three cases, the supplements were compared with a placebo and found to be ineffective.

Manufacturers of dietary supplements are responsible for the safety of their products, but they not required by the FDA to prove that their products are effective. This minimal, or in some cases, complete lack of information makes the following studies all the more important to people who have been purchasing them for years.

Saw Palmetto for Prostate Symptoms

Saw palmetto is an herbal extract used by more than 2 million men in the U.S. to treat the symptoms of benign prostatic hyperplasia (BPH), or enlarged prostate.  The newly published clinical trial randomly assigned 225 men who had moderate to severe symptoms of BPH to take either 160 milligrams of saw palmetto twice a day, or a placebo. Neither the study participants nor the doctors who cared for them knew who was taking saw palmetto and who was taking a placebo.

After one year of treatment, the research team led by Stephen Bent, MD, and colleagues at several California medical institutions found the men taking saw palmetto showed no more improvement in urinary symptoms or quality of life than those who had been taking a placebo. This study was published in the February 9 issue of The New England Journal of Medicine. It was funded by grants from the U.S. National Institute of Diabetes and Digestive and Kidney Disease and the National Center for Complementary and Alternative Medicine.

Melatonin for Sleep Disorders

Melatonin is a hormone that is secreted by the pineal gland, a tiny cone-shaped organ in the brain that regulate the body’s sleep/wake cycles. Melatonin supplements have long been sold to the public as a way to hasten sleep or reduce the symptoms of jet lag.

Last month, the British medical journal, BMJ, published a review of all trials in which melatonin supplements were compared with placebo in people with sleep problems. Altogether there were 15 trials in which 524 people had been randomly assigned to take either melatonin or a placebo for three months or less. The supplement did not improve the study participants’ ability to fall asleep or reduce the sleep deprivation associated with jet lag. Nor did melatonin help people whose sleep problems were the result of working the night shift. The researchers determined that melatonin is safe for short-term use, but there is little information beyond that.

This review was funded by grants from the U.S. Agency for Research and Healthcare Quality and the Center for Complementary and Alternative Medicine.

Glucosamine and Chondroitin Sulfate for Knee Osteoarthritis

Glucosamine and chondroitin are substances found naturally in joints. Glucosamine is believed to repair the cartilage and chondroitin provides elasticity to the cartilage. Glucosamine and chondroitin sulfate are the two most widely used supplements in the U.S.

The newly published trial included 1,583 people with moderate to severe osteoarthritis of the knee who were randomly assigned to take 1500 milligrams of glucosamine,  or 1200 milligrams of chondroitin sulfate, or  both glucosamine and chondroitin, or 200 milligrams of celecoxib, sold as Celebrex, or a placebo each day for 24 weeks.

The research team led by Daniel O. Clegg, MD, University of Utah School of Medicine, Salt Lake, found that glucosamine and chondroitin sulfate alone or in combination did not reduce knee pain. There was some improvement in symptoms reported by the people taking Celebrex. While the majority of those on glucosamine plus chondroitin did not benefit, a minority on this combination did experience significant pain relief.

The researchers also noted a high rate of response among the people who had been taking the placebo. 61% of them reported reductions in pain; whereas drug trials typically show about 30% of the people taking a placebo report improvements.

This study, published last month in The New England Journal of Medicine, was funded by the National Center for Complementary and Alternative Medicine and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Maryann Napoli, Center for Medical Consumers ©
March 2006

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Doubts About Safety of Flu Vaccine in Kids

Posted by medconsumers on October 1, 2005

Last winter, researchers found that influenza vaccines provide no benefit to babies under age two years. In children over the age of two, vaccines showed a modest reduction in cases of influenza. But there is no evidence that vaccines can prevent the serious complications that are the primary justification for vaccinating children. That was the conclusion of a review of all relevant studies published last February in the British journal, Lancet.

The authors of this review, Tom Jefferson, MD, and colleagues at the Cochrane Collaboration, recently wrote a follow-up in a letter to the editor of The Lancet. They reported that the safety of influenza vaccines given to babies and children is unknown. Incredibly, most of the trials they reviewed were not designed to assess serious adverse reactions.

Given the fact that the U.S. and Canada now recommend flu vaccines for all children older than six months, this news is extremely disturbing. The review published last winter focused solely on the question of how well flu vaccines work for children over six months. After the review was published, Dr. Jefferson and colleagues took on the equally important question of vaccine safety.

At issue are two types of vaccines: inactivated and live attenuated (nasal spray). Where it concerned the  inactivated vaccine, the research on safety was pitiful. Only one trial exists; it was small (35 participants) and conducted 30 years ago. All other safety studies of inactivated vaccine were in children three years or older. When the reviewers looked at safety studies of the live attenuated vaccine, Dr. Jefferson explained in an e-mail interview, “We found clear evidence of systematic  suppression (non-reporting) of safety data.” Worse, he said that the authors of the trials did not have access to safety data from their own trials!  “Do U.S. parents know all this?” asked Dr. Jefferson,  “I do not think so.”

One trial in this review stood out from the rest. With 10,000 participants, it included a chart showing a nearly double number of “medical adverse events” among the vaccinated kids, compared with the unvaccinated. When Dr. Jefferson and colleagues noticed that fewer than half of these events had been adequately identified, they wrote to request the missing data, first from the lead author and then from the final authority, the vaccine manufacturer MedImmune. The company’s response: “MedImmune does not provide safety data to outside parties.”

Noting that serious omissions like this are common, Dr. Jefferson and colleagues wrote, “An incomplete or fragmented evidence base could hinder identifications of rare and serious adverse events.”

The U.S. Centers for Disease Control and Prevention, known as the CDC, is the most influential promoter of vaccinations for children (and everyone else). Presently, flu vaccines for babies and children are recommended; they are not mandated, as are other childhood vaccinations. At the CDC Web site, you will find no cautions regarding the missing information about the safety of vaccines for children. Nor will you find any evidence that the agency is aware of the review published last winter by Dr. Jefferson and colleagues. The CDC Web site’s main message: “The single best way to protect against the flu is to get vaccinated each fall.” And babies 6-23 months are listed as one of the priority groups for flu vaccines.

“Their rate of influenza-related hospitalization is similar to that of people 65 and older,” warned Carolyn Buxton Bridges, MD, medical epidemiologist in the CDC’s National Immunization Program. By e-mail, Dr. Bridges was asked for proof that flu vaccines reduce the rate of hospitalization in babies  6-23 months. “I fully acknowledge that the number of randomized studies is very limited and none published to date  have evaluated the benefits of the vaccine in terms of preventing influenza hospitalization. However, ample data exists that the vaccine prevents laboratory confirmed influenza in young children 6-23 months. And, if you prevent the initial infection, you would also prevent the complications that would follow the infection.”

Consumer advocate Barbara Loe Fisher, co-founder and president of the National Vaccine Information Center, has a different perspective. “Children these days get so many vaccines that they almost always get them together on the same day. Use of the flu vaccine in combination with other childhood vaccines in babies this young amounts to a national medical experiment on American babies. The science should precede the policy and not the other way around.”

Dr. Bridges was asked whether the CDC will warn parents about the lack of safety data and the fact that some vaccine companies refused to release their data to Dr. Jefferson and colleagues. She partially addressed only the second half of the e-mailed question. “As to why the researchers [sic: vaccine companies] will not share their data with Dr. Jefferson, I cannot comment.”

As for proof of safety Dr. Bridges points to 40 years of vaccine usage and the Vaccine Adverse Event Reporting System, established in 1990, under the joint administration of the CDC and the FDA. (The CDC’s own assesment of VAERS in 2003 found, “multiple limitations” to be associated with this “passive surveillance system [in which] reports of events are voluntarily submitted by those who experience them, their caregivers, or others.” Underreporting and unconfirmed diagnoses are the major problems. )

Dr. Jefferson identified the problem in using the CDC as a credible source of advice, though it is the one used most frequently by the media. “The CDC, which should have a neutral public health role, is in fact a vaccine advocate, with all the good and bad things that that entails.”

Bottom Line

The Lancet review of all relevant trials published last winter by Dr. Jefferson and colleagues found no evidence to support the CDC position. Asked to summarize the findings of this review, which was published as the 2004/05 flu season was just about over, Dr. Jefferson responded,“Our review showed that influenza vaccines below the age of two have the same effects as placebo. Beyond the age of two, they may be effective in preventing cases of influenza, but we found no evidence that they could prevent serious outcomes (death, hospitalization, pneumonia etc).”

The CDC’s Dr. Bridges conceded that there is, as yet, no proof that flu vaccines will reduce the rate of serious complications in young children. Due to incomplete reporting of adverse reactions to influenza vaccines in clinical trials involving children, safety questions remain unanswered.

Maryann Napoli, Center for Medical Consumers ©
October 2005

Posted in Children's Health | Tagged: , | Comments Off

Influenza Vaccines, Influenza Drugs – Both Losing Effectiveness

Posted by medconsumers on October 1, 2005

This flu season got off to an unusual start with a well-publicized study that found influenza vaccines are far less effective for the elderly than previously thought. A second study found a worldwide viral resistance to several drugs that are widely prescribed once a person comes down with the flu. Both were published this month in the British journal, The Lancet.

The first study was a systematic review of the evidence for the effectiveness of influenza vaccines in people aged 65 years and older. Studies in this review were conducted in many countries over the course of 37 years. People living in long-term care facilities were more likely to benefit with a 42% reduction in deaths caused by influenza and pneumonia. Whereas elderly people living on their own had a more modest 30% reduction in hospitalizations for pneumonia. The review was conducted by Tom Jefferson, MD, and colleagues at the Cochrane Collaboration, an international organization that evaluates studies to determine the efficacy of medical care.

While the reductions in deaths and hospitalizations described above appear praiseworthy, they are actually more modest than meets the eye—something that will become clear once you learn how flu vaccine studies are conducted. These reductions are also more modest than those quoted by the Centers for Disease Control and Prevention. This federal agency, known as the CDC, is the most influential promoter of flu vaccines.

It is possible that this review by Jefferson and colleagues might initiate a more honest public discussion about the issue. And this, in turn, might lead to improvements in vaccines. Not only is the impact of vaccines oversold to the public but there is also a lot of confusion over the definition of influenza.

Influenza and Influenza-like Illness

Each flu season between 5% and 20% of the population comes down with symptoms of the illness. A vaccine, at best, will only lower the chances of getting influenza. What isn’t explained to the public is this: in any given year, the vaccine has some proven effectiveness only against influenza A or B. This is what researchers call influenza, and it afflicts fewer than 15% of all people who appear to have the flu. All other forms of the flu are called influenza-like illness. Both types cause exactly the same symptoms: headache, fever, muscle aches, cough, and runny nose. Doctors have no way of distinguishing the two types without a blood test or a culture.

Every year, the vaccine formulation changes.  According to the CDC Web site, “three viruses (two subtypes of influenza A viruses and one influenza B virus) are selected to go into the flu vaccines for the following fall and winter. Usually, one or two of the three virus strains in the vaccine are changed each year.” The selection is based on a combination of educated guesswork, flu outbreaks in Asia, and recommendations of the World Health Organization. “This guesswork actually works quite well in healthy adults, [but] not so well in the elderly,” warned Dr. Jefferson, the lead author of the new review in an e-mail interview.

How well a vaccine will protect you against influenza depends on the virus strains selected that year and whether it matches the circulating viruses in your environment. At the section of its Web site for health professionals, the CDC gives a high rate of effectiveness for vaccines. For example, the MMWR (Morbidity and Mortality Weekly Report) 2004, states, “When the vaccine and circulating viruses are antigenically similar [emphasis ours], the influenza vaccine prevents influenza illness among approximately 70%–90% of healthy adults under age 65 years and children one year and older 77%-90%.” Note the carefully worded qualification.

In other words, if influenza A or B viruses are circulating in your part of the world and the vaccine happens to be the right match, then the vaccine might lower your chances of getting influenza by 90%. The vaccine, however, provides no protection if people in your immediate vicinity have influenza-like illness.

Drugs to Treat Influenza A

The second study, published in the same issue of The Lancet, found that influenza A viruses have developed a resistance to drugs that are widely prescribed to people once they have flu-like symptoms. Rick Bright of the CDC and colleagues analyzed 7,000 blood samples of flu viruses collected from people around the world and found a resistance to Symmetrel, Flumadine, and others in a drug class called admantadine. (One of these drugs is given immediately on the presumption that the patient has influenza A because the drug must be taken within the first 48 hours of the onset of symptoms. Until recently, these drugs shortened the duration of influenza A by 30 hours.)

Vaccine Review’s Puzzling Results

The first study—the review by Jefferson and colleagues—had a puzzling finding about the vaccines’ effect on elderly people not living in nursing homes. When the reviewers combined data from 15 studies, they found that inactivated influenza vaccines were ineffective against influenza-like illnesses, influenza, or pneumonia, but prevented up to 30% of hospitalizations for pneumonia. How can vaccines be useless in preventing illness but helpful in preventing hospitalizations for pneumonia? “We are not sure,” answered Dr. Jefferson. “Our  [finding] was based on non-randomized studies, which are well known for producing overestimates of effectiveness. The real effect is likely to be more modest.”

This qualification didn’t make it into the CDC “talking points” memo that went out to the media on the day Dr. Jefferson’s review made headlines across the country. The CDC first acknowledged, “Vaccine effectiveness is not 100%,” but then went on to uncritically assert, “The [review] did demonstrate that influenza vaccine is effective in preventing the complications and death from influenza in older persons, both in the community and in long term care facilities.

But qualifications were present throughout the review by Jefferson and colleagues. Phrases like “with good vaccine match and high viral circulation” preceded findings of vaccine effectiveness. When asked how often the vaccine matches the viruses circulating in any given flu season, Dr. Jefferson said, “Unless there is a known epidemic underway in the surrounding community and someone is doing real time surveillance (i.e., testing of specimen), never. The problem with such studies is that they are logistically very difficult, as we acknowledge in our review.”

As for that honest discussion about vaccines and how well they work, Dr. Jefferson identified a major stumbling block. “Vaccines are a business, like any other. The only difference is that governments are co-sponsors with industry,” he explained. “Overestimation of the threat by the target diseases, suppression of data on possible adverse events, and exaggeration of effectiveness are frequent, as the case of influenza vaccines demonstrates. In the case of population vaccination programs, both government and industry have conflicts of interest. Beware.”

Maryann Napoli, Center for Medical Consumers ©
October 2005

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Flu Vaccines Do Not Work For Kids Or The Elderly

Posted by medconsumers on March 1, 2005

Flu vaccines provide virtually no benefit to children. That’s the conclusion of a new review of all relevant studies. Interestingly, the news comes at a time when some health officials have begun to recommend the vaccination of all children in order to prevent them from passing on the flu to their elderly relatives. The review follows on the heels of a study that looked at three decades’ worth of data and found that vaccines for the elderly are not as effective as previously thought. And contrary to conventional medical wisdom, vaccines do not seem to reduce flu-related deaths in elderly people.

To determine the value of flu vaccines to children, Tom Jefferson, MD, and colleagues at the Cochrane Collaboration looked at over a thousand studies. They selected 14 high-quality clinical trials in which vaccinated children had been compared with unvaccinated children. The combined results of these 14 trials were reported in the British journal The Lancet (2/26/05). Here’s the conclusion: “We recorded no convincing evidence that vaccines can reduce mortality, [hospital] admissions, serious complications, and community transmission of influenza.”

The best the Cochrane reviewers could come up was this: “Vaccines were somewhat effective at reducing school absence…” Though the U.S. Centers for Disease Control (CDC) and Prevention advises flu vaccines for babies 6-23 months because they tend to suffer more complications once they get the flu, no evidence supports the recommendation. The Cochrane reviewers found that vaccines had little effect on bronchitis, ear infections, and hospitalizations, compared with the babies given placebo vaccines. In short, the CDC recommendations are irresponsible given the fact that the only two studies that involved babies found no benefit and little is known about adverse effects of these vaccines for babies.

Benefit to Elderly overrated
Now for the importance of flu vaccines to the elderly. A new comprehensive study cast doubt on the widespread belief that flu vaccines save lives (Archives of Internal Medicine, 2/14/05). Though the authors work for a federal government health agency, they produced evidence that failed to support CDC recommendations.

Lone Simonsen, PhD, and colleagues at the National Institute of Allergy and Infectious Diseases conducted a review of 33 consecutive flu seasons, from 1968 to 2001. The authors began their report with an acknowledgement that an accurate assessment of flu-related deaths is virtually impossible because few cases are confirmed with blood tests. And the viral infection is usually cleared from the body before the appearance of complications that cause death. For these reasons, the authors had to use a special statistical method to estimate flu-related deaths and deaths from all causes among elderly Americans over the three-decade-period.

Here is what Dr. Simonsen and colleagues found:

  • The number of flu-related deaths among elderly Americans increased steadily during the 33-year-period, despite the fact that their acceptance of flu vaccinations also steadily increased. For example, only 20% of all elderly Americans had a flu shot in 1980, compared with 65% in 2001.
  • There was a decline in flu-related deaths among people 65-74 years in the decade after the 1968 flu pandemic because people had naturally acquired immunity due to exposure to the emerging viruses of that period. The increasing flu vaccine coverage after 1980, however, did not correlate with a decline in flu-related deaths.
  • The over-all death rate for people over 85 during flu seasons did not change over the 33-year-period. Dr. Simonsen and colleagues cite earlier research that might provide an explanation for why flu vaccines did not reduce the flu-related deaths in “the very elderly” after 1980 when vaccine coverage began to increase, “…antibody responses following influenza vaccination decline sharply after age 65 years and a clinical trial involving subjects 60 years or older…found that the efficacy of influenza vaccine in preventing influenza illness was lower in people older than 70 years.”

Because fewer than 10% of all winter deaths can be attributed to the flu in any year during this study’s three-decade period, the authors conclude that vaccination’s benefit to elderly people has been substantially overestimated.

Maryann Napoli, Center for Medical Consumers ©
March 2005.

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Vitamin D Deficiency: Cause Of Many Ailments

Posted by medconsumers on January 1, 2005

The Institute of Medicine brought experts together recently to explore the question of whether the RDA or recommended daily allowance, of vitamin D has been set too low. The impetus for the occasion was the mounting evidence for this vitamin’s role in preventing common cancers, autoimmune diseases, type 1 diabetes, heart disease, and osteoporosis. Furthermore, studies have shown that vitamin D deficiency is common in the U.S. Because the typical symptoms are aching bones and muscle discomfort, vitamin D deficiency is often misdiagnosed as fibromyalgia or chronic fatigue syndrome, according to Michael F. Holick, MD, PhD, of the Boston University School of Medicine.

Dr. Holick has conducted a review of all vitamin D studies, which was published in the December 2004 issue of the American Journal of Clinical Nutrition. Vitamin D has become the vitamin of the moment, possibly because researchers in this field want to raise the RDA again. And Dr. Holick’s review, which was funded by the U.S. National Institutes of Health, certainly supports the move.

For most Americans, sunlight provides the lion’s share of our vitamin D requirements because we eat few foods that naturally contain vitamin D, such as cod liver oil and oily fish (salmon, sardines, and mackerel). But many Americans do not meet the minimum requirement of sun exposure. What’s more, vitamin D deficiency is more pronounced among people living at higher latitudes, such as the New England States, especially in winter.

Dr. Holick and colleagues conducted a 2002 study at the Boston Medical Center , which found that, by the end of the winter, 32% of students and doctors, aged 18 to 29 years, were vitamin D deficient. Winter isn’t the only problem because, year-round, many people spend a lot of time indoors or slather themselves with sunscreen when they do go outside. So it was not too surprising that another study conducted in Boston found a high degree of D deficiency in white (30%), Hispanic (42%) and black (84%) elderly people at the end of August. Another study found that 38% of nursing home residents were vitamin D deficient.

Much of the sun avoidance and excessive sunscreen use is attributed to public education campaigns by dermatologists warning about skin cancers. It should be noted, however, that the most deadly form of skin cancer, melanoma, is not entirely related to sun exposure. In fact, Dr. Holick describes the sunlight-melanoma link as baffling because the disease rarely occurs on the face and hands. Instead, melanoma is more likely to appear on areas of the body that are not as exposed to the sun.

Obesity is yet another cause of vitamin D deficiency, according to Dr. Holick, who found that even when dietary vitamin D intake and sun exposure are adequate, the vitamin becomes unavailable because it becomes stored in the large amount of body fat. Aging skin requires more sun exposure. A 70-year-old exposed to the same amount of sunlight as a 20-year-old will only make 25% of the vitamin D that the young person can make. Breastfed infants are deficient in vitamin D because human milk is deficient in vitamin D. Dr. Holick offered this explanation for why deficiencies are widely overlooked: During the standard blood work-up, doctors tend to focus on the blood calcium levels, and if they are normal, doctors incorrectly assume their patients are getting enough D.

Why the seemingly sudden interest in vitamin D when intriguing research goes back over a half century? In 1949, a researcher published his observation that people who live at higher latitudes, such as New Hampshire , Vermont , and Massachusetts , had a higher incidence of cancer deaths, compared with people living in southern states, such as Texas , Georgia , and Alabama.

In a telephone interview, Dr. Holick was asked why other researchers didn’t pick up on this study and look further. “It was an interesting observation, but people didn’t take epidemiology seriously,” he answered. “Little attention was paid to it until the 1980s when other researchers reported that colon and breast cancer rates were higher for those living at higher latitudes in the U.S. ” Even then, the finding was not taken seriously until researchers understood the mechanism for how the breast, colon, and prostate activate vitamin D and use it to regulate cell growth, which Dr. Holick explained as a process that is, “keeping cell growth in check and possibly preventing the cell from becoming autonomous and developing into an unregulated cancer cell.”

After the paper explaining the mechanism was published in the British journal The Lancet, much more research attention began to be paid to vitamin D. And after 1999, many more observational studies were published showing a link between vitamin D deficiency and several chronic diseases. For example, there are higher rates of multiple sclerosis in people who live at higher latitudes; and another study showed vitamin D intake is inversely associated with rheumatoid arthritis.

In a 2001 study published in The Lancet, children treated with 2,000 IU daily of vitamin D from their first birthday onward had an 80% decreased risk of developing type 1 diabetes throughout the next 20 years. And in the last few years, several studies have been published indicating a link between schizophrenia and decreased exposure to sunlight. Dr. Holick’s review states that animal studies have successfully shown that type 1 diabetes, rheumatoid arthritis, and multiple sclerosis can be prevented using mice prone to these diseases.

To Dr. Holick, who is an endocrinologist, it is clear from studies like these (and many more that go unmentioned in this article for lack of space) that vitamin D should no longer be thought of only as the nutrient necessary for the prevention of rickets in young children. He said that his work has been instrumental in the vitamin D fortification of several common foods, including milk products, bread, and orange juice.

In the telephone interview, Dr. Holick was asked whether an increase in the RDA for vitamin D was imminent, given the fact that the Institute of Medicine , a division of the National Academy of Science, recently held a meeting on the topic. “No, it usually takes 10 to 15 years to change an RDA,” he answered. “A huge bureaucratic system is involved.” In the meantime, he and other vitamin D researchers recommend a minimum of 1,000 IU vitamin D daily. This increase, he explained, will maximize the absorption of calcium.

As for the risk of overdose, Dr Holick said, “You’d have to take 10,000 to 20,000 IU daily to approach toxicity.” Is the type of vitamin D important? “Multivitamins usually have D 2 which comes from yeast, but it’s probably only 20-40% as effective as D 3 ,” which, he believes is better and longer lasting.

Then there’s the question of what constitutes an adequate amount of sunlight: “Five to ten minutes of exposure of the arms and legs or the hands, arms and face two or three times a week,” stated Dr. Holick, adding a way of determining the right timing, “25% of the time that it would take to cause a light pinkness to the skin.”

For More Information:
Read Dr. Holick’s book, co-authored with Mark Jenkins and written for the general public, The UV Advantage ( New York : Simon & Schuster/ibooks , 2003).

Maryann Napoli, Center for Medical Consumers ©
January 2005

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Do Cholesterol-Lowering Drugs Benefit Women?

Posted by medconsumers on June 1, 2004

Many doctors have come to believe that the cholesterol-lowering drugs called statins (Lipitor, Zocor, Pravachol, Mevacor, Crestor) are safer than low-dose daily aspirin. That becomes apparent whenever statins are featured in the media as a wonder drug for the prevention of heart disease. In fact, there’s a growing consensus among cardiologists that all adults should take a statin whether or not they are at high risk.

Yet women have been underrepresented in the major clinical trials in which people with and without heart disease were randomly assigned to take a statin or a placebo (dummy pill) every day for several years. Women made up less than one-third of all the study participants. Put that together with the fact that women under the age of 75 years have a low rate of heart attack and stroke. Add this disturbing bit of news from University of British Columbia researchers who conducted a thorough review of the five prevention clinical trials: only two of the five trials released their data regarding the serious adverse effects* suffered by the study participants who were taking statins. Working with what they had, that is, the data from only two of the statin trials, the researchers found that statins did not prolong life for men or women. Worse, the benefit of taking statins (a reduced rate of non-fatal heart attacks and stroke) was offset by an increase in the serious adverse events. Until all the statin trials release their serious adverse effects data, the public will not know whether these drugs are safer than low-dose aspirin.

The sparse information that people receive about cholesterol treatment was unintentionally but aptly illustrated recently by one of the country’s top medical journals. The Journal of the American Medical Association, or JAMA, regularly publishes a “patient page,” which amounts to a layman’s translation of one of the more important papers published in each issue.

The May 12, 2004 issue of JAMA contained a review of all trials in which women with high cholesterol had been randomly assigned to take a drug or a placebo. (Most of the trials involved a statin.) Judith M.E. Walsh, MD, MPH, and Michael Pignone , MD, MPH conducted the review. Their conclusion: For women without heart disease, drugs did not prolong life or reduce the odds of dying of heart disease. The drug may reduce non-fatal cardiac events (heart attack, stroke, etc.), but “current evidence is insufficient to determine this conclusively.” For women with heart disease, drugs do not affect mortality but will reduce non-fatal events.

Turn to the patient page in the same issue of JAMA, and none of this important information can be found. Instead, six sentences are devoted to statins explaining how they work; the need for regular lab tests to check for statin-induced liver damage; the possibility of muscle damage, etc. The reader will find nothing about the drugs’ effectiveness (or ineffectiveness) in preventing or treating heart disease. The rest of the page was given over to the usual information about exercise and smoking cessation. Worse, it has outdated information about the importance of a low-fat diet; despite the fact that a review of all relevant studies found that it has little effect on heart disease prevention (see below). The patient page is intended for physicians to photocopy and give to their patients.

And what about the unreported serious adverse effects of statin drugs? Not a mention in the patient page, of course, but there it was in the “comments” section of the JAMA article. At the end of their review, Drs. Walsh and Pignone discuss possible explanations for why statins do not prolong life for women with heart disease. The drugs reduce the odds of dying of heart disease, but that benefit is canceled by a higher rate of death from other causes.

“Possible explanations include chance, the limitation that not all studies reported both heart disease and total mortality… Another potential explanation might be an increase in a competing cause of mortality, for example, an increase in hemorrhagic stroke with cholesterol-lowering therapy. However, information on the causes of non-heart disease mortality is not available for all the trials, so this possibility cannot be proven. [emphasis added] Publication of cause-specific mortality for many of the larger trials could help to clarify the association between cholesterol-lowering therapy and total mortality.”

There you have it, the full story is not yet available on the safety of cholesterol-lowering drugs, though these trials were published years ago. Traditionally, researchers design trials to answer specific questions. In this case: Does this drug reduce the rate of heart attacks and strokes or the rate of cardiovascular death? But the drug itself might cause deaths from other causes, and as Drs. Walsh and Pignone wrote, not all studies reported deaths from other causes. These concerns are relevant to men, as well.

As for the doctors who say that statins are safer than aspirin, they might one day be proven correct. But it took more than 100 years to get the full story on aspirin. (In fact, there might be more to learn.) Gastrointestinal bleeding and rarely, hemorrhagic stroke are both potentially fatal side effects of chronic use of aspirin, even at low doses. And the dangers of giving aspirin to children who have flu or chicken pox have only been known to be associated with the rare risk of Reye’s syndrome for less than 30 years.

*Serious adverse effects are any untoward medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, or results in persistent or significant liability.

Maryann Napoli, Center for Medical Consumers (C)

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Second Thoughts about Aspirin a Day to Prevent Heart Attacks

Posted by medconsumers on January 1, 2004

A baby aspirin a day keeps a heart attack away. This widely accepted health practice was seriously undermined at an advisory committee meeting of the Food and Drug Administration (FDA, held in December 2003. The FDA advisory committee voted overwhelmingly to reject a petition from the Bayer Corp. to approve aspirin for reducing the risk of a first heart attack.

Though an estimated 20 million Americans already take low-dose aspirin daily to prevent a heart attack, this is an off-label use—that is, the aspirin manufacturers have not received FDA approval for this particular indication. FDA approval is required, however, once an aspirin manufacturer plans to advertise the drug for this use. And once approval is granted, the drug’s packet insert must be rewritten to inform consumers of the new indication.

Bayer’s petition made the FDA Cardiovascular and Renal Drugs Advisory Committee take a critical look at the five trials (One trial compared aspirin with vitamin E) in which people without heart disease took either aspirin or a placebo (a dummy pill). Altogether there were more than 55,000 participants at anywhere from low to high risk for a heart attack. Here is what the cardiologists and other experts on the committee found in the way of benefit: Aspirin produced about a 32% reduction in non-fatal heart attacks. [Translation: An estimated 3% of all moderate-risk people will have a heart attack in the next five years. Daily low-dose aspirin therapy will reduce their odds to about 2%.] The benefit is given in terms of a five-year period because the trials lasted four to seven years.

Several things troubled the FDA committee members about the results of these trials: Aspirin did not have any mortality reduction benefit; nor did it reduce the odds of having an ischemic stroke, which is, arguably, the most feared consequence of heart disease. Yet aspirin has the potential for causing another, less common type of stroke called hemorrhagic stroke, which is a rupture of a blood vessel in the brain.

One committee member who voted to reject Bayer’s petition is Steven Nissen, MD, Medical Director of the Cleveland Clinic Cardiovascular Coordinating Center. In a telephone interview, Dr. Nissen explained, “The data [from the five trials] were terribly weak.” You always have to weigh the trade- offs , he said, referring to hemorrhagic stroke as the major concern.

But the aforementioned 32% reduction in non-fatal heart attacks applies to the combined total of all the study participants, most of whom were men with differing levels of risk. The committee hit a snag once it came to individuals. Dr. Nissen said that he and other committee members were concerned that daily aspirin, if taken by people at a low enough risk, could cause more harm than good. Asked to define “low enough risk,” he explained that there was too much uncertainty to answer the question. “No one in the world can answer the question of who benefits and who doesn’t, and if there is no answer, then how could I vote to approve?” he asked.

The fact that women were underrepresented in the five trials (only 20% of all participants) also troubled Dr. Nissen. “It may be that the risks exceed the benefit for women,” he said, “but we simply don’t know—there is not enough data.” Still, Dr. Nissen was careful to stress that he was not against aspirin therapy for everyone, suggesting that people talk over the decision with their physicians. The FDA advisory committee “took a lot of heat,” said Dr. Nissen, referring to its decision to turn down Bayer’s petition and thus reject the prevailing medical view that aspirin therapy is good for just about everyone. “We were called flat earthers ,” he said.

The FDA is not obligated to follow the decisions made by its advisory committees, but the agency usually does. The committee’s decision, though entirely appropriate, illustrates how the current system works against consumers who want to become fully informed before they go on lifelong drug therapy. Approval would have meant a rewrite of the drug’s packet insert to include the new indication. And this, in turn, would have compelled the advisory committee to identify the appropriate group of people for whom the benefit of aspirin therapy clearly outweighs the risks. The evidence from the five trials did not provide the answer; therefore, 20 million people will continue to take daily aspirin without knowing anything about the uncertainties of the supporting research.

The advisory committee’s concerns can be contrasted with the practice guidelines aimed at physicians and published in 2002 by the U.S. Preventive Services Task Force. The Task Force concluded that the number of “cardiac events” prevented by aspirin therapy far exceeded the number of hemorrhagic strokes caused by aspirin therapy. This, too, is based on the combined results of the same five trials. When the Task Force tried to break things down for individuals, it came up with this estimation for moderate-risk men and women: “For 1,000 patients with a 3% risk of having a heart attack in the next five years, aspirin would prevent eight heart attacks but would cause one hemorrhagic stroke and three major gastrointestinal bleeding events.”

Where it concerns low-risk people, the Task Force is in agreement with the FDA advisory committee: MMMM
“…patients at low risk for coronary heart disease probably do not benefit from and may even be harmed by aspirin because the risk for adverse events may exceed the benefits…” (Annals of Internal Medicine, 1/15/02).

For More Information:

  • Go to www.med-decisions.com to see one method used by the Task Force to identify different levels of risk for a heart attack. The Task Force used an additional assessment tool based on the risk information from the Framingham Heart Study, which has since become outdated.
  • The transcript of the December 8-9, 2003 meeting of the Cardiovascular and Renal Drugs Advisory Committee is likely to be posted on the Internet in February or March. Go to www.fda.gov and click into “Advisory Committees.” Then go to this specific committee and its meeting date.

Maryann Napoli
January 2004

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Osteoporosis: How Effective is Prevention?

Posted by medconsumers on December 1, 2003

by Maryann Napoli

When osteoporosis emerged as a major health problem in the 1980s, experts in the field believed that the devastating fractures suffered by some women in old age could be prevented. Most of the diet and exercise advice was aimed at mid-life women who were warned that they would be rapidly losing bone right after menopause. The bone loss, they were told, was largely due to the body’s declining level of estrogen. In time, bone density testing became a rite of passage for many menopausal women.

The increased awareness of osteoporosis plus the overemphasis on estrogen’s role in bone loss had the unfortunate consequence of making mid-life women believe that an inevitable hip fracture loomed in the near future. Once bone density testing continued to show bone loss, something had to be done. And that something often turned out to be a lifelong prescription for estrogen. This hormone drug proved itself many times over to be good at stopping bone loss. However, estrogen had never been proven to reduce the fracture rate.

That proof arrived in 2002 with the results from the Women’s Health Initiative (WHI) trial. Estrogen, in combination with progestin, slightly reduced the rate of hip fractures in the WHI. Unfortunately, this hormone combination is too risky for lifelong use because the WHI showed that it raised the risk of developing blood clots, stroke, breast cancer and Alzheimer’s disease. (Progestin was added to the regimen to protect the uterus from estrogen’s cancer-causing effect.)

Now, the tide of expert opinion is slowly changing its focus away from mid-life women to those of advanced age. As Dr. Susan Love said in her Menopause & Hormone Book, “The usual line is that prevention is always better than treatment, and this has certainly driven the use of HRT [hormone replacement therapy] in postmenopausal women. This may not actually be the case.”

Dr. Love sees the newer osteoporosis medication–from a drug class known as the bisphosphonates (brand names: Fosamax, Actonel, Didronel)–as safer alternatives to 30 years on estrogen.

Bisphosphonates will modestly reduce the hip and spinal fracture rate, but the published evidence for this benefit is primarily confined to elderly women with low bone mineral density and at least one other major risk, such as a previous spinal fracture.

An osteoporosis-related hip fracture is rare in women younger than 70 (the average age at which it occurs in women is 79), and only 18% of all white women will ever have a fracture. One reason to reserve treatment for high-risk older women is the lack of long-term information–beyond seven years–about bisphosphonate’s safety and continued effectiveness.

The shift in thinking about osteoporosis prevention is reflected in the revised recommendations about when to start bone density testing. Several medical organizations, such as the National Osteoporosis Foundation, now suggest that women not start until age 65, unless they are at extremely high risk. Some osteoporosis researchers have made a case for the quality of bone strength as the more important indicator of a future fracture than bone density. There is no available test for bone strength.

How Good are the Best Drugs?
The bisphosphonates cannot improve bone strength, but they are the only drugs proven to reduce the rate of hip and spinal fractures. Actonel, for example, modestly reduced the fracture rate in a study of 10,000 high-risk elderly women with low bone density or osteoporosis and at least one risk factor for hip fracture, such as an unsteady gait. At three years, there was a 1% lower rate of hip and spinal fractures among the women taking Actonel than those taking the placebo. Interestingly, the three-year fracture rate was low in these supposedly high-risk women, even among those not taking the drug. Overall, the fracture rate was 4% among those taking a placebo versus 3% among those on Actonel (New England Journal of Medicine, 2/1/01).

The fracture prevention value of bisphosphonates in younger women is yet to be demonstrated. In another trial, 1,609 postmenopausal participants, aged 45 to 59 years, were chosen because they did not have osteoporosis. Short-term treatment with Fosamax (5 mg/daily or 2.5 mg/daily) was compared with estrogen plus progestin. The idea was to see whether Fosamax had a sustained effect once the drug was discontinued. The study was paid for in part by a grant from Merck, maker of Fosamax. Some of the women in the Fosamax group took the drug for two years and were than switched to a placebo; others remained on the drug for the four-year duration of the study.

At the end of this study, bone loss had been prevented in those taking Fosamax and in those on estrogen/progestin. Continuous Fosamax treatment, however, was more effective in preventing bone loss than the shorter two-year regimen. The fracture rate is low in this age group, and the study lasted only four years; therefore, this trial could not show that Fosamax reduced fractures (Annals of Internal Medicine, 12/21/99).

What about Diet and Exercise?
Osteoporosis research has clearly shown that increased calcium intake and certain exercises will stop bone loss and/or improve bone density, but few studies have lasted long enough to prove the ultimate goal of fracture reduction. In 2002, the Cochrane Library published an updated review of all studies that assessed the value of exercise in preventing osteoporosis. The reviewers conclusions favored aerobics, weight bearing and resistance exercises as the most effective in increasing bone mineral density of the spine. And walking was effective for the hip. Of the few studies that showed fracture reduction, two found walking to be the best for older men and women. In fact, a moderate amount of walking (2-4 hours a week), and even standing, reduced the hip fracture rate. Interestingly, one study showed that the people who spent more time walking did not have a lower rate of fractures than those did just the 2-4 hours a week.

Where diet is concerned, emphasis has been almost entirely—-and perhaps, inappropriately—-placed on calcium. For over 20 years, women have been advised to increase their daily calcium intake with diet and/or supplements to 1,000 mg daily, and then raise it to 1,500 mg after age 50.

Studies show that calcium supplements will stop bone loss, but they typically did not last long enough to provide information about fractures. As for any fracture-reduction benefit from high dietary calcium intake, the famed Nurses’ Health Study produced some bad news. About 77,000 of the participants were singled out because they did not take calcium supplements. All were between the ages of 30 and 55 years in 1980 when they began filling out extensive questionnaires biannually about their health habits. After 18 years, there was a modest but significantly increased incidence of fracture among the women who reported the highest dietary intake of calcium, primarily from milk and other dairy foods (American Journal of Public Health, 6/97).

To determine whether this study was an aberration, Diane Feskanich, D.Sc., and colleagues at Harvard Medical School, looked at all the trials in which calcium supplementation was compared to a placebo, as well as the longer studies, such as the Nurses’ Health Study, in which women were asked about their diet, calcium supplement usage and other health habits while being followed for many years. The Harvard researchers concluded that the first category of trials, those that lasted only a few years, typically showed that calcium supplements reduced bone loss. But “the longer observational studies did not generally find a lower risk of hip fracture with higher-calcium diets” (American Journal of Clinical Nutrition, 2/03).

In a telephone interview, Dr. Feskanich was asked why women continue to be told to increase their calcium intake. “Calcium’s importance is overrated––we have a strong milk industry [in this country], and the U.S. Department of Agriculture was started with the mission to promote the idea that certain foods, especially dairy foods, must be consumed,” she answered, adding the importance of the Dairy Council, which has had a major influence on doctors as well as the general public. Contradictions abound. “We know from worldwide population studies that the high-calcium intake is associated with high hip fracture rates–Scandinavian countries, for example,” Dr. Feskanich continued, noting that Asian and Mediterranean countries with very low calcium intake have low fracture rates.

Vitamin A
The emphasis on the importance of calcium has led many women to drink low-fat or non-fat milk to prevent osteoporosis, a practice that is counterproductive, according to Dr. Feskanich. Drawing, once again, from 18-year data provided by the Nurses’ Health Study, Dr. Feskanich and her colleagues found that a certain type of vitamin A, is associated with an increase in hip fractures (JAMA, 1/2/02). They identified the fortification of dairy products as the chief culprit. “Because the fat has been removed, the vitamin A has to be put back,” explained Dr. Feskanich, adding that people typically take a one-a-day vitamin supplement and eat a fortified breakfast cereal, and they might eat a power bar–all of which are fortified with vitamin A.

The fortification is usually done with the cheaper form of the vitamin called retinol, the type that is not good for bones in the long term, according to Dr. Feskanich. You can get beta carotene [the other form of vitamin A] from orange and yellow vegetables and fruits, she added, “and you can get plenty without eating animal products or taking a supplement.” Consumption of just one multivitamin often provides an excessive amount of vitamin A if the label says 5,000 IU with retinol as the major source. But some vitamin manufacturers have begun to reduce or eliminate retinol from their products.

To Dr. Feskanich and other nutrition researchers, the current RDA of 5,000 IU daily of vitamin A is too high, a point made in the editorial that accompanied her study. The editorial cites, approvingly, the Institute of Medicine’s new recommendations for vitamin A intake as 800 IU daily for men and 700 IU daily for women.

Vitamin D
At the end of the telephone interview, Dr. Feskanich said, “I can’t say that there is no benefit to calcium, but I think there’s a bigger benefit from vitamin D.” Unfortunately, Dr. Feskanich and colleagues found that only a few studies focused on this vitamin as a way to prevent fractures. One of them, published in 2003 in the British Medical Journal, had over 2,600 participants, aged 65 to 85 years at the onset. All were living in the community (as opposed to a nursing home) and had been randomly assigned to take a placebo or vitamin D.

The study was conducted entirely by mail. The participants were sent one capsule containing 100,000 IU of vitamin D3 (cholecalciferol) or a placebo every four months for five years. The total fracture incidence was reduced by 22%. The research team led by Daksha P. Trivedi cautioned that the fracture incidence was extremely low even in those who had been taking the placebo, possibly due to the fact that most of the participants were men.

This was a small pilot study, and as such cannot be considered the last word on the role of vitamin D and fracture prevention. Dr. Trivedi and colleagues wrote, “The results, nonetheless, indicate that isolated vitamin D supplementation prevents fractures.” In discussing their findings, Dr. Trivedi and colleagues wrote that the every-four-month dose of 100,000 IU averages out to be a daily equivalent of 800 IU of vitamin D. And this might explain why their results were different from those of earlier trials, which used a lower dose (400 IU) and found no fracture-reduction benefit due to vitamin D.

The rapid responses to this article, or letters to the editor, can be read at no charge on the British Medical Journal’s Web site (www.bmj.com, see March 1,2003). Several raised the concern about the potential toxicity of high doses of vitamin D. This was answered by one of the study’s co-authors, Kay Tee Shaw, who wrote that several earlier trials showed that extremely high doses of vitamin D are safe. In one Scandinavian trial, nursing home residents were safely given single-dose injections of 300,000 IU of vitamin D annually for four to five years.

Dr. Feskanich’s response to the same concern was that vitamin D is fat-soluble so people don’t need to take a little bit every day. What’s more, “vitamin D is stored in the liver, and this is good,” she explained, because elderly people don’t metabolize vitamins well as they age, and the body’s capacity to produce vitamin D when exposed to sunlight also declines with age. Her studies found that women typically consume less than the recommended intake of vitamin D. Therefore, they should consider supplement use or dark fish consumption.

Maryann Napoli is the associate director of the Center for Medical Consumers in New York City.
December 2003

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