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Women’s Health Initiative Study
WOMEN'S HEALTH INITIATIVE STUDY
To the editor:
Although letters to the editor do not require authors to disclose potential conflicts of interest, I have chosen to do so. I am a basic scientist involved in research on estrogens for the past 36 years. The research carried out in my laboratories has been supported by the Medical Research Council of Canada (MRC, CIHR), National Cancer Institute, Ontario Treatment and Research Foundation, other granting agencies, and pharmaceutical drug companies including the manufacturers of the estrogen/progestin combination used in the WHI study. I have no personal financial arrangements with any company. I was shocked and dismayed at the manner in which the National Institutes of Health (NIH) investigators, involved in the Women's Health Initiative (WHI) study dealing with hormone replacement therapy (HRT) using combined conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA), released the data to the general public on July 9,2002. Dr. C. Lenfant, Director of the National Heart, Lung, and Blood Institute of NIH, stated in the press release that a "26% increase in breast cancer risk is too high a price to pay, even if there were a heart benefit." The magnitude of the panic, horror, and apprehension such media releases raised in the minds of millions of women throughout the world who are on estrogen replacement therapy (ERT) or HRT will be difficult to ascertain. The urgent and widespread manner in which the data was released to the general public first, via press releases, is, to my knowledge, unprecedented, and has resulted in more harm than good. Mter careful review of the actual publication in the Journal o/the American MedicalAssociation (JAMA),l I found little statistically significant information, particularly regarding coronary heart disease (primary beneficial outcome) and breast cancer (primary adverse outcome), to warrant such a widespread and rapid release of this data. The main results presented are essentially confirmatory of several earlier observational studies and are detailed below. As regards breast cancer, more than 50 observational studies2 have shown a small increase in the risk for breast cancer, particularly after prolonged use ofERT or HRT. The WHI study now confirms this risk, citing 8 more cases of invasive breast cancers per 10,000 women/year in a randomized controlled trial. The premature termination of the HRT (estrogen and progestin) trial after just 5.2 years was not due to a significant increase in breast cancer numbers, as the general public thinks, but because the number of cases of breast cancer had reached a pre-specified number that crossed the designated safety boundary. This safety limit JOGC
was, for obvious reasons, set low. Based on this, the authors had no choice but to terminate the study. The WHI trial showed a small increase in early adverse effects related to coronary heart disease (CHD), but the preset safety boundaries had not been reached. This small early increase of 7 more CHD events per 10,000 women/year has also been previously observed in a number of HRT observational studies. 3-5 Observational studies 4 have indicated that the risk for stroke was increased in postmenopausal women on HRT. The WHI study now confirms this adverse outcome, citing 8 more events per 10,000 women/year. Although the previously observed small increase in thrombosis in women using ERT or HRT was mainly based on data derived from oral contraceptive use,6 similar observations have been reported with ERT or HRT use by postmenopausal women.? The WHI data for HRT also confirm this welIknown adverse effect and are not surprising. Therefore, as far as the main adverse outcomes are concerned, the WHI results confirm previous observational findings, clearly indicating the validity of observational studies. Where osteoporosis is concerned, a number of observational 8 and clinical8 studies have reported that ERT or HRT increases bone density and reduces vertebral and hip fracture rates 9 ,10 and it is well established that estrogen is the best documented agent for prevention of postmenopausal osteoporosis, The WHI study confirms this very important beneficial effect ofHRT, and the data further indicate that HRT is a primary prevention that reduces the hip fracture rate, as evidenced by their finding of 5 fewer hip fracture cases per 10,000 women/year. It is important to note that newer, non-estrogen drugs for the treatment of osteoporosis have been shown to reduce fracture rates only in women with pre-existing osteoporosis or previous bone fractures, and thus their role in primary prevention of postmenopausal osteoporosis remains to be established, Observational studies ll have indicated that postmenopausal HRT or ERT reduces the risk of colorectal cancer. The WHIIHRT trial also confirms this data, and further indicates that HRT can be beneficial as a primary prevention of colorectal cancer, citing 6 fewer colorectal cancer cases per 10,000 women/year. 1 A large number of women in the WHI trial dropped out of the study: 42% from the HRT group and 38% from the placebo group, 1 These numbers exceeded the design projections. No reasons were given for this extremely high dropout rate, which is one of the major weaknesses of this incomplete trial. In view of the high dropout rate, the very small number of either adverse or beneficial events, and the fact that the hazard ratio estimates for invasive breast cancer (1.26) and CHD (1.29) are SEPTEMBER 2002
low, these estimates should be used with extreme caution. Moreover, their clinical significance is questionable. The results of the WHI randomized controlled trial are, indeed, reassuring, in that HRT use by postmenopausal women is associated only with a small increase in breast cancer. I The WHI studyl reports that the hazard ratio (HR 1.15) for the global index (Figure 4 in their paper), comparing the increase in adverse effects with the benefits ofHRT, indicated "possible narrowing of the difference by year 6"; however, they minimize the significance of this observation by further stating that "HR estimates tend to be unstable beyond 6 years after randomization." Perhaps this was another reason to terminate the study early. If this is true, the same can be said for all of their estimates. It is important to note the large inconsistencies in the year-to-year estimates (Table 4 of their paper). For example, for CHD, the HR was 0.99 for year 4, while that for year 5 was 2.38, and that for year 6 and later was 0.78. Similarly, they showed a more than two-fold difference for breast cancer: 2.54 for year 5 and 1.12 for year 6 or later. The women selected for the WHI randomized controlled trial on HRT were between the ages of 50 and 79 years and considered to be healthy. Table 1 of the WHI paperl indicates that the average age was 63.3 years and only 33% of the women were between 50 and 59 years, a time when many women consi4er ERT or HRT because of their menopausal symptoms. Nearly 70% of the women were overweight and, of these, half were obese (body mass index ~ 30),36% were treated for hypertension, and only 50% had never smoked. Perhaps this is an acceptable definition of "healthy women" in the USA, but it may not be applicable to the rest of the world. The WHI study data indicate that the overall mortality in the treatment and placebo groups was the same (0.52 annualized %) and, more importantly, there was also no significant difference in CHD or breast cancer deaths in the two groups. The WHI study dealing with ERT (CEE) alone, in 10,739 women who have had a hysterectomy, has also been ongoing for 5.2 years, and this randomized controlled trial is being continued. Unfortunately, the WHI investigators provided no information in their press releases regarding the incidence of adverse CHD events and breast cancer in this arm of the study. This information might have at least relieved the fear in women who are being treated with ERT alone, and may have provided some clues regarding the role of estrogen alone and combined estrogen and progestin in the observed adverse and beneficial effects. This brief review of the main findings of the WHI trial released to the media and published in JAMAl clearly indicates that the study provided very little, if any, new information that merited such a rapid and widespread release. Observational studies have been criticized for potential biases, including the socalled "Healthy User Bias." In view of the above brief discussion, the WHI randomized controlled HRT trial l has confirmed what JOGC
numerous observational studies have been telling us all along: long-term HRT use is associated with a small increase in breast cancer; early adverse events related to CHD, stroke, and thromboembolism; prevention of osteoporosis; reduction in fracture rate; and reduction in the risk for colon cancers. In view of this vigorous confirmation of observational data by the WHI randomized controlled trial on HRT, it is premature to discard the other consistent findings from observational studies that long-term ERT or HRT use is associated with a significant long-term cardiovascular benefit, along with the well-established facts that this therapy relieves menopausal symptoms and vaginal atrophy, prevents osteoporosis, and improves the overall quality oflife of postmenopausal women. Considering all of the benefits and risks together, every woman and her physician will be able to more appropriately determine her risk benefit ratio associated with HRT. Dr. Bhagu Bhavnani Professor of Obstetrics and Gynecology. University of Toronto and St. Michael's Hospital.Toronto. Ontario
REFERENCES I.
Writing Group for the Women's Health Initiative Investigators. Risk and benefits of estrogen plus progestin in healthy postmenopausal women.J Am Med Assoc 2002;268:321-33. 2. Beral V. Bull D. Doll R. Key T, Peto R. Reeves G. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52.705 women with breast cancer and 108.411 women without breast cancer. Lancet 1997;350: I047-59. 3. Hulley S. Grady D. Bush T, Furberg C. Herrington D. Riggs B. et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAm Med Assoc 1998;280:605-13. 4. Grodstein F, Manson JE. Colditz GA,Wiliett WC. Speizer FE. Stampfer MJ. A prospective. observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000; 133:933-41. 5. Grodstein F, Manson JE. Stampfer MJ. Postmenopausal hormone use and secondary prevention of coronary events in the Nurses' Health Study. A prospective observational study. Ann Intern Med 200 I; 135: 1-8. 6. Vessey MP, Doll R.lnvestigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J 1968;2: 199-205. 7. Castellsague J. Perez Gutthann S. Garcia Rodrigues LA. Recent epidemiological studies of the association between hormone replacement therapy and venous thromboembolism: a review. Drug Safety 1998; 18: I 17-23. 8. Gallagher Jc. Estrogen: prevention and treatment of osteoporosis. In: Marcus R. Kelsey J. Feldman D. Osteoporosis. San Diego: Academic Press; 1994. p. 1191-1208. 9. Weiss NS. Ure CL. Ballard JH.Wiliiams AR. Daling JR. Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen. N Engl J Med 1980;303: I 195-8. 10. Kiel DP, Felson DT, Anderson JJ,Wilson pw. Moskowitz MA. Hip fracture and use of estrogens in postmenopausal women. The Framingham Study. N Engl J Med 1987;317: I 169-74. I I. Grodstein F, Newcomb PA. Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 1999; I06:574-82. JULY 2002
To the editor:
Although letters to the editor do not require authors to disclose potential conflicts of interest, I have chosen to do so. I am a basic scientist involved in research on estrogens for the past 36 years. The research carried out in my laboratories has been supported by the Medical Research Council of Canada (MRC, CIHR), National Cancer Institute, Ontario Treatment and Research Foundation, other granting agencies, and pharmaceutical drug companies including the manufacturers of the estrogen/progestin combination used in the WHI study. I have no personal financial arrangements with any company. I was shocked and dismayed at the manner in which the National Institutes of Health (NIH) investigators, involved in the Women's Health Initiative (WHI) study dealing with hormone replacement therapy (HRT) using combined conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA), released the data to the general public on July 9,2002. Dr. C. Lenfant, Director of the National Heart, Lung, and Blood Institute of NIH, stated in the press release that a "26% increase in breast cancer risk is too high a price to pay, even if there were a heart benefit." The magnitude of the panic, horror, and apprehension such media releases raised in the minds of millions of women throughout the world who are on estrogen replacement therapy (ERT) or HRT will be difficult to ascertain. The urgent and widespread manner in which the data was released to the general public first, via press releases, is, to my knowledge, unprecedented, and has resulted in more harm than good. Mter careful review of the actual publication in the Journal o/the American MedicalAssociation (JAMA),l I found little statistically significant information, particularly regarding coronary heart disease (primary beneficial outcome) and breast cancer (primary adverse outcome), to warrant such a widespread and rapid release of this data. The main results presented are essentially confirmatory of several earlier observational studies and are detailed below. As regards breast cancer, more than 50 observational studies2 have shown a small increase in the risk for breast cancer, particularly after prolonged use ofERT or HRT. The WHI study now confirms this risk, citing 8 more cases of invasive breast cancers per 10,000 women/year in a randomized controlled trial. The premature termination of the HRT (estrogen and progestin) trial after just 5.2 years was not due to a significant increase in breast cancer numbers, as the general public thinks, but because the number of cases of breast cancer had reached a pre-specified number that crossed the designated safety boundary. This safety limit JOGC
was, for obvious reasons, set low. Based on this, the authors had no choice but to terminate the study. The WHI trial showed a small increase in early adverse effects related to coronary heart disease (CHD), but the preset safety boundaries had not been reached. This small early increase of 7 more CHD events per 10,000 women/year has also been previously observed in a number of HRT observational studies. 3-5 Observational studies 4 have indicated that the risk for stroke was increased in postmenopausal women on HRT. The WHI study now confirms this adverse outcome, citing 8 more events per 10,000 women/year. Although the previously observed small increase in thrombosis in women using ERT or HRT was mainly based on data derived from oral contraceptive use,6 similar observations have been reported with ERT or HRT use by postmenopausal women.? The WHI data for HRT also confirm this welIknown adverse effect and are not surprising. Therefore, as far as the main adverse outcomes are concerned, the WHI results confirm previous observational findings, clearly indicating the validity of observational studies. Where osteoporosis is concerned, a number of observational 8 and clinical8 studies have reported that ERT or HRT increases bone density and reduces vertebral and hip fracture rates 9 ,10 and it is well established that estrogen is the best documented agent for prevention of postmenopausal osteoporosis, The WHI study confirms this very important beneficial effect ofHRT, and the data further indicate that HRT is a primary prevention that reduces the hip fracture rate, as evidenced by their finding of 5 fewer hip fracture cases per 10,000 women/year. It is important to note that newer, non-estrogen drugs for the treatment of osteoporosis have been shown to reduce fracture rates only in women with pre-existing osteoporosis or previous bone fractures, and thus their role in primary prevention of postmenopausal osteoporosis remains to be established, Observational studies ll have indicated that postmenopausal HRT or ERT reduces the risk of colorectal cancer. The WHIIHRT trial also confirms this data, and further indicates that HRT can be beneficial as a primary prevention of colorectal cancer, citing 6 fewer colorectal cancer cases per 10,000 women/year. 1 A large number of women in the WHI trial dropped out of the study: 42% from the HRT group and 38% from the placebo group, 1 These numbers exceeded the design projections. No reasons were given for this extremely high dropout rate, which is one of the major weaknesses of this incomplete trial. In view of the high dropout rate, the very small number of either adverse or beneficial events, and the fact that the hazard ratio estimates for invasive breast cancer (1.26) and CHD (1.29) are SEPTEMBER 2002
low, these estimates should be used with extreme caution. Moreover, their clinical significance is questionable. The results of the WHI randomized controlled trial are, indeed, reassuring, in that HRT use by postmenopausal women is associated only with a small increase in breast cancer. I The WHI studyl reports that the hazard ratio (HR 1.15) for the global index (Figure 4 in their paper), comparing the increase in adverse effects with the benefits ofHRT, indicated "possible narrowing of the difference by year 6"; however, they minimize the significance of this observation by further stating that "HR estimates tend to be unstable beyond 6 years after randomization." Perhaps this was another reason to terminate the study early. If this is true, the same can be said for all of their estimates. It is important to note the large inconsistencies in the year-to-year estimates (Table 4 of their paper). For example, for CHD, the HR was 0.99 for year 4, while that for year 5 was 2.38, and that for year 6 and later was 0.78. Similarly, they showed a more than two-fold difference for breast cancer: 2.54 for year 5 and 1.12 for year 6 or later. The women selected for the WHI randomized controlled trial on HRT were between the ages of 50 and 79 years and considered to be healthy. Table 1 of the WHI paperl indicates that the average age was 63.3 years and only 33% of the women were between 50 and 59 years, a time when many women consi4er ERT or HRT because of their menopausal symptoms. Nearly 70% of the women were overweight and, of these, half were obese (body mass index ~ 30),36% were treated for hypertension, and only 50% had never smoked. Perhaps this is an acceptable definition of "healthy women" in the USA, but it may not be applicable to the rest of the world. The WHI study data indicate that the overall mortality in the treatment and placebo groups was the same (0.52 annualized %) and, more importantly, there was also no significant difference in CHD or breast cancer deaths in the two groups. The WHI study dealing with ERT (CEE) alone, in 10,739 women who have had a hysterectomy, has also been ongoing for 5.2 years, and this randomized controlled trial is being continued. Unfortunately, the WHI investigators provided no information in their press releases regarding the incidence of adverse CHD events and breast cancer in this arm of the study. This information might have at least relieved the fear in women who are being treated with ERT alone, and may have provided some clues regarding the role of estrogen alone and combined estrogen and progestin in the observed adverse and beneficial effects. This brief review of the main findings of the WHI trial released to the media and published in JAMAl clearly indicates that the study provided very little, if any, new information that merited such a rapid and widespread release. Observational studies have been criticized for potential biases, including the socalled "Healthy User Bias." In view of the above brief discussion, the WHI randomized controlled HRT trial l has confirmed what JOGC
numerous observational studies have been telling us all along: long-term HRT use is associated with a small increase in breast cancer; early adverse events related to CHD, stroke, and thromboembolism; prevention of osteoporosis; reduction in fracture rate; and reduction in the risk for colon cancers. In view of this vigorous confirmation of observational data by the WHI randomized controlled trial on HRT, it is premature to discard the other consistent findings from observational studies that long-term ERT or HRT use is associated with a significant long-term cardiovascular benefit, along with the well-established facts that this therapy relieves menopausal symptoms and vaginal atrophy, prevents osteoporosis, and improves the overall quality oflife of postmenopausal women. Considering all of the benefits and risks together, every woman and her physician will be able to more appropriately determine her risk benefit ratio associated with HRT. Dr. Bhagu Bhavnani Professor of Obstetrics and Gynecology. University of Toronto and St. Michael's Hospital.Toronto. Ontario
REFERENCES I.
Writing Group for the Women's Health Initiative Investigators. Risk and benefits of estrogen plus progestin in healthy postmenopausal women.J Am Med Assoc 2002;268:321-33. 2. Beral V. Bull D. Doll R. Key T, Peto R. Reeves G. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52.705 women with breast cancer and 108.411 women without breast cancer. Lancet 1997;350: I047-59. 3. Hulley S. Grady D. Bush T, Furberg C. Herrington D. Riggs B. et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAm Med Assoc 1998;280:605-13. 4. Grodstein F, Manson JE. Colditz GA,Wiliett WC. Speizer FE. Stampfer MJ. A prospective. observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000; 133:933-41. 5. Grodstein F, Manson JE. Stampfer MJ. Postmenopausal hormone use and secondary prevention of coronary events in the Nurses' Health Study. A prospective observational study. Ann Intern Med 200 I; 135: 1-8. 6. Vessey MP, Doll R.lnvestigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J 1968;2: 199-205. 7. Castellsague J. Perez Gutthann S. Garcia Rodrigues LA. Recent epidemiological studies of the association between hormone replacement therapy and venous thromboembolism: a review. Drug Safety 1998; 18: I 17-23. 8. Gallagher Jc. Estrogen: prevention and treatment of osteoporosis. In: Marcus R. Kelsey J. Feldman D. Osteoporosis. San Diego: Academic Press; 1994. p. 1191-1208. 9. Weiss NS. Ure CL. Ballard JH.Wiliiams AR. Daling JR. Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen. N Engl J Med 1980;303: I 195-8. 10. Kiel DP, Felson DT, Anderson JJ,Wilson pw. Moskowitz MA. Hip fracture and use of estrogens in postmenopausal women. The Framingham Study. N Engl J Med 1987;317: I 169-74. I I. Grodstein F, Newcomb PA. Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 1999; I06:574-82. JULY 2002