I read with great consternation the article “Raloxifene. Not better than estrogen,” translated from the French La revue Prescrire. As an article in a journal that is designed to keep Canadian family physicians up-to-date on the latest medical information, it leaves much to be desired. Without going into great detail, below is an outline of the most recent, evidence-based information on raloxifene, in particular, as it compares with estrogen. For more details, I refer readers to a review article on raloxifene, published in another Canadian peer-reviewed journal.

  1. In Canada, raloxifene (eg, Evista) is indicated for preventing and treating osteoporosis in post-menopausal women. Data to support this indication come from the MORE study (Multiple Outcomes of Raloxifene Evaluation). This was a double-blind randomized placebo-controlled study of 7705 postmenopausal women with osteo-porosis. It demonstrated that, after 3 years of therapy, raloxifene reduced the incidence of new vertebral fractures by 55%. Raloxifene also reduced the incidence of new vertebral fractures in women with pre-existing vertebral fractures by 30%. The 4-year data from the MORE study were presented at the American Society for Bone and Mineral Research meeting in Toronto, Ont, and are almost iden-tical to the 3-year results.The MORE study is the first adequately powered, randomized placebo-controlled trial to demonstrate that an estrogenlike agent reduces the risk of new vertebral fractures. This is level 1 evidence. There are no comparable data on the ability of estrogen to reduce fractures. The evidence for estrogen to reduce fractures is level 3 only, from observational studies and from one small (n=75) randomized, prospective study of the 100 mg estradiol patch.
  2. There is no evidence from randomized, prospective studies that estrogen reduces cardiovascular disease. In fact, recent studies suggest the opposite, at least for secondary prevention. Both estrogen and raloxifene reduce a number of surrogate markers of cardiovascular risk, although they each have their own unique profiles. Studies are under way to determine whether raloxifene will affect cardiovascular events.
  3. It is well-known that the use of unopposed estrogen results in uterine stimulation, necessitating the concomitant use of progesterone. In fact, more recent evidence shows that the use of progesterone does not completely negate the potential stimulatory effects of estrogen. Raloxifene has been shown in numerous studies to have an antiestrogen effect on the uterus, with no evidence of uterine stimulation and no need to use concomitant progesterone.
  4. Numerous studies have revealed a slightly increased risk of breast cancer with estrogen use, with a more recent study suggesting the concomitant use of progesterone increases the risk further. The MORE study has demonstrated a 76% reduction in the incidence of new invasive breast cancers with raloxifene compared with placebo, not 1% as indicated in the article. This is by no means sufficient to support an indication for raloxifene for preventing breast cancer, but it shows a safety profile for raloxifene superior to that for estrogen.
  5. Raloxifene does not treat hot flashes associated with menopause. In fact, in the MORE study, incidence of hot flashes while using raloxifene was 9.7% compared with 6.4% while using placebo. Estrogen remains the treatment of choice for hot flashes associated with menopause. Raloxifene should not be used to treat hot flashes in symptomatic early postmenopausal women.
  6. The issue of ovarian cancer, which was raised by a few poorly informed individuals when raloxifene was first introduced to the market, has been shown to be completely unfounded. The discovery of ovarian tumours in rodents that were given raloxifene for their entire reproductive lives, when their ovaries were susceptible to hormonal influences, is in no way similar to the situation in postmenopausal women, whose ovaries no longer respond to hormonal changes. Furthermore, the more common types of ovarian tumours in humans are adenocarcinomas, which are not responsive to hormonal changes, while ovarian tumours in rodents are. As well, the MORE study and others have been tracking the incidence of ovarian cancer, and there is no indication whatsoever of an increased risk of ovarian cancer with the use of raloxifene. There is no reason to “watch the ovaries” with raloxifene.
  7. Raloxifene was not “obtained by chemical operation on tamoxifen” as stated in the article. Tamoxifen is a triphenylethylene compound, and raloxifene is a benzothiophene, a completely different and distinct chemical entity.
  8. Hyperglycemia was not observed with greater frequency in the raloxifene group than in the placebo group in the MORE study, as reported in the article. The self-reported incidence of diabetes was greater in the raloxifene groups than in placebo groups, but these reports were not substantiated by glucose levels. In fact, glucose levels and HbA1c were similar in the placebo and raloxifene groups.

—Loren D. Grossman, MD, FRCPC, FACP Associate Vice President, Clinical Research Eli Lilly Canada Inc Scarborough, Ont by mail


We consider that our account of the results of the MORE trial is correct. Our wording was more precise than that used in your letter, which argues in terms of the relative risk, exaggerates the effect rather than the absolute risk, and gives a more realistic notion of the true benefit. You state that the benefit is 55% in terms of the incidence of a first vertebral collapse, whereas we wrote that, in the clinical trial, 2.6% of women using raloxifene had at least one vertebral collapse, compared with 4.5% of women using placebo (a benefit of only 1.9% in absolute values).

We recently reviewed the various consensus statements and expert recommendations on fracture prevention in elderly women. All consider estrogen as the first-line drug. Health professionals are therefore right to wait for the results of trials comparing raloxifene with estrogen on the basis of clinical end points. The only trial available was unfavourable to raloxifene in terms of mineral bone density, a surrogate end point.

No one denies that the level of evidence is low. However, your references are incomplete. The trial involving 75 women concerned secondary prevention. You also fail to mention a placebocontrolled trial of transdermal estradiol in primary prevention, which involved 123 women treated for 2 years. We reviewed this trial in a previous article.

We did not state that estrogen reduces cardiovascular risk. We simply reported on changes in cholesterol levels on estrogen and raloxifene.

Regarding endometrial cancer, our article does not deny the lower incidence using raloxifene relative to estrogen, but we were unable to find any data on the real benefit in absolute values.

Your statement that the risk of breast cancer is reduced by 76% on raloxifene is highly misleading, as it is again based on the relative risk. The figures are 13 cases using raloxifene and 27 using placebo, or incidence rates of 0.3% versus 0.7%, as we stated.

We agree that raloxifene increases the frequency of hot flashes, unlike estrogen. We stated that data on ovarian cancer in animals cannot be extrapolated to humans. Nevertheless, these data should not be overlooked. The possible risk of an increase in ovarian cancer can be ruled out only by close scrutiny of drugs.

The relation between raloxifene and tamoxifen is indicated in the report by the European Agency for the Evaluation of Medicinal Products. It also appears in Martindale—the Complete Drug Reference.

The report of the MORE trial indicates a higher frequency of aggravation of pre-existing diabetes, or onset of diabetes, in patients using ralox-ifene than in those using placebo.

We see no reason to modify our stated judgment on raloxifene.

—Dr Bruno Toussaint Editor-in-chief La revue Prescrire Paris, France

Dr Fred Fallis

It is with great sadness that I read1 of the passing of Dr Fred Fallis. I was a locum tenens in Fred’s practice in North York, Ont, from 1970 to 1973 and what a general practice it was!

would run back and forth from the emergency room, the family practice clinic, the St George St Outreach Clinic, or a meeting at the old Toronto General Hospital, back to Fred’s office on Avenue Rd. Several times I dropped in for supper with his wife Lois and the emerging Fallis family, which was, for me, always special.

Working with Fred was always fun. We would have a heck of a time kibitzing and throwing around the gaff. Always a wink and a spurt of jocularity accompanied Fred as we went about our practice. He was the penultimate conversationalist and friend. With a smile, he could disarm you and get to the quick of the problem while seemingly having all the time in the world to listen.

I regret not keeping more in contact with Fred and nurse Joan Reeve as I have traveled my medical path. Yet Fred was a man, mentor, and special human being with whom time and distance melted as soon as you saw him. He had the knack of kindling the inner fire of comradeship in a split second.

In the early meetings of forming the Department of Family Medicine at the Toronto General Hospital, I believe it was Fred’s energy and keenness that kept us on track. Thank you, Fred, for being there and for always sharing a part of yourself. We will miss you.

—Leonard Levine, MD, CCFP Ottawa, Ont by mail

Housecalls are where it’s at

I loved your article on housecalls. Amen.

Another advantage of making housecalls is being able to check medications-often Aunt Mabel’s drugs from 10 years ago are still around.

Some other tricks I have used are to do housecalls only on Friday morn¬ings to treat myself after a long, hard week. I also talk to family and patients and tell them I cannot rush out from a busy office for emergencies. This avoids unfulfilled expectations.

—John W. Crosby, MD, FRCPC, MCFP(EM) cambridge, Ont by mail

Time to fess up, authors!

As an expatriate Certificant (1969) and Fellow (1978) of the College of Family Physicians of Canada, I religiously read my Canadian Family Physician as soon as I get it. The August 2000 issue contains a thorough, comprehensive, and interesting article1 on management of genital her¬pes by Drs Tetrault and Boivin.

Drug costs in America are escalating at an incredible rate. Last year the aver¬age increase in drug costs was reported to be 17%, more than four times the background rate of inflation. The cost of drugs was recently shown to have exceeded the cost of hospitalization in America.

The retail ethical drug market is a fascinating antithesis to the famous “economics 101” concept of the “efficient market.” An efficient market, of course, is where informed buyers occupying all points of the economic scale are free to buy an object in a market with a variety of suppliers. This is widely believed to produce the most efficient result: all buyers are generally able to find products that suit their needs and price range. For example, in America automobile buyers are able to pay $275000 for a Rolls Royce or Ferrari or $500 for a 15-year-old junkyard special. All participants receive value for the transaction, and there is no need for government intervention in these markets.

In the retail drug market, although articles about specific drugs fill the pages of medical journals published all over the world and virtually the only advertising in these journals is highly sophisticated and technically high-quality advertisements for various drugs, nowhere does one ever see an allusion to price. The drug industry successfully keeps both patients and doctors completely in the dark about drug prices. I have been the object of many thousands of drug retailing experiences, and I have never heard the cost of a drug ever mentioned unless I ask for it.

Every article ever written about a specific drug is financed by the company that makes the drug. The studies that underlie these issues are financed by the drug company (and at significant cost for expenses associated with arranging the study and for a handsome premium to the physician or physician group carrying out the study). In America, this has become a lucrative sideline in many physicians’ practices as a way to cope with the income compression associated with managed care. Doctors who write the articles to expand on these studies are virtually always under contract or have some other financial arrangement with the company, such as the speaker’s bureaus.

Finally, the studies are always written in such a way as to completely ignore cost issues and avoid head-to-head comparisons with similar drugs in that class. The only studies that objectively compare drugs are studies subsidized by some national objective body, such as the National Institutes of Health.

Table 1 shows the comparative cost of the drugs touted in the article1 for treatment regimen for genital herpes (their Table 4). I have included the cost at our local pharmacy of the course of therapy identified in the article. For example, treatment of the acute herpes episode will range from about $33 for generic acy-clovir to $263 for valacyclovir. There is no evidence that one of these drugs offers any advantage over the other, except for a change in frequency from five times a day for acyclovir versus twice a day for valacy-clovir. How many people do you think would pay $263 rather than $33 if they were using their own money?

Another issue is what sense does it make to treat one episode of recurrent herpes that, in general, lasts 6 days, for which treatment reduces the duration of illness by about a day, and where for most people the symptoms are just a local irritation?

Table 1. Treatment regimens for genital herpes





Acyclovir 200 mg 5 times daily for 10 days



Acyclovir (Zovirax) 200 mg 5 times daily for 10 days



Valacyclovir 500 mg twice daily for 10 days*



Famciclovir 250 mg 3 times daily for

5 to 10 days*




Acyclovir 200 mg 5 times daily for 5 days



Acyclovir (Zovirax) 200 mg 5 times daily for 5 days



Valacyclovir 500 mg twice daily for 5 days



Famciclovir 125 mg twice daily for 5 days




Acyclovir 400 mg twice daily



Acyclovir (Zovirax) 400 mg twice daily



Valacyclovir 500 mg daily**



Famciclovir 250 mg twice daily



* Not approved for this indication in Canada. ** For subjects with 10 or more recurrences yearly, dosage should be 1000 mg daily or 250 mg twice daily.

Canadian Family Physician already has one of the best, objective, and readable drug evaluations in the North American primary care literature with “Prescrire.” Canadian Family Physician could improve on an already great journal by requesting that every author of a drug-related article declare all pharmaceutical company relationships in detail and that these be identified at the beginning of the article. Of course, that would not solve the problem of specific reference to drug-related papers in the bibliography, but one can assume that they are all written under drug company sponsorship.

—L.B. McNally, MD Dallas, Tex by mail

Source: Can Fam Physician. 2001 January

Category: Drugs / Tags: Canada, Drugs, genital herpes

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