Bioidentical Hormones - U.S. Senate Special Committee on Aging

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197 HORMONE THIERAPY USE AND RISK OF CARDIOVASCULAR DISEASE that estrogen may delay the onset of the earliest stages of atherosclerosis, which are more likely to be present in younger women, bilt it may be ineffeclive or even trigger events in the presence of existing advanced lesions such as those found in older women.' The potential existence of a window of opportunity to reduce cardiovascular disease is supported by animal and laboratory studies.' Compared with observational studies of hormone therapy use among healthy women stich as the Nurses' Health Study, most women in the randomized hormone trials were older and the majority commenced study hormones more than a decade after menopause began.'-',' Subgroup analyses in the 2 WHI trials of hormone therapy suggested a nonsignificant reduction in risk of CHD in women aged 50 to 59 years in the trial of CEE' or in women with less than 10 years since menopause in the trial of CEE + MPA. 'Risk of stroke did not appear to be reduced in these subgroups.'" 0 The numbersof events in the subgroups in the individual trials were too small to provide definitive answers but the similar direction of the findingssupports the idea that pooling the trials could yield clearer In this secondary analysis, statistical power was improved by the use of techniques that allow combining the trial data to examine trends in the effects of hormone therapy on CHD and stroke across categories of age and years since menopause. These results could apply to a population similar to the women enrolled in the WHI trials, which included 40% of women taking unopposed estrogen (CEE) or placebo and 60% of women taking estrogen plus progestin (CEE + MPA) or placebo. Total mortality and a predefined global index were examined to capture the overall effects of hormone therapy on disease outcomes. Combined hormone therapy trial analyses and subgroup analyses by age were prespecified in the WHI protocol; other analyses were not prespecified The subgroup and secondary analyses are ex- 1466 IAMA, Apol 4, 2007-x .9 27.. 13 (Ri t depatei) ploratory; however, given that these are therapy or first had vasomotor sytnp- the best available data, the ipotential toms fte, hot flashes, night sweats). For clinical implications ofour finsdings also women who had a hysterectomy with- are examined. out bilateral oophorectomy at age 50 METHODS Study Participants and Out coines years or older but no use of hormone therapy or symptoms, the age at menopause was defined as the age when the The WHI trials enrolled 27 347 pre- hysterectomywasperformed. flthe al- dominantly healthy postmei nopausal gonthm defined an age at menopause women aged 50 to 79 years from Sep- as older than 60 years, it was recoded tember 1993 to October 1998lat4O US as 60 years Anymisclassification of age clinical centers based on hmysterec- at menopause is likely to he nondiffer- tomy status. Of these womei i, 10 739 ential atid would tend to bias the re- had undergone a hysterecu omy and sults toward the null. Age at menowere randomized to 0.625 mg 1dofCEE pause could not be defined (due to or placebo and 16608 had rtot had a missing values) in 1420 (8 5%) women hysterectomy and were randc,mized to who had not had a hysterectomy and 0.625 mgld of CEE plus 2.5S mg/d of in 1610(15%)womenwhohadahys- MPA or placebo. Details have Ieenpub- terectomy. These women wvere ex- fished elswhere.t " cluded from the years-since meno- The trials were reviewed and ap- pause analyses, which included 24 317 proved by the institutions I review participants. boards at each clinical ceniter and all Studypanicipantscompletedaques- participants provided wr itten in- tionnaire at baseline thatvincluded a formed consent. All outcomes werecen- probe-for the presence of vasomotor trally adjudicated. The mam out- symptoms (hot flashes or night sweats) comes for the current anall rses were during the prior 4 weeks If present, par- CHD (defined as nonfatal myocardial ticipants were asked how bothersome infarction, CHD death, or silent myo- the symptom was. Mild indicated that cardial infarction) and strolce Other the symptom did not interfere with outcomes were mortality antI a global usual activities; moderate, the symp- index (defined as the first o0currence tom interfered somewhat with usual ac- of CHD, stroke, puimonat ry embo- tivities; and severe, the symptom was lism. breast cancer, colorectral cancer, so severe that usual activities could not endometrial cancer I CEE + i IPA trial be performed. only], hip fracture, or death ft-om other Event rate comparisons were based causes) used for trial monitoring. Clini- on the intent-to-treat principle using cal events that were seIf-rTe sorted by failure time methods. For a given out- participants prior to unblindi ingat trial come, the nome to event was the num- closure and subsequently adjudicated ber of days from randomization to the were included. Due to the co mpressed timeline for the initial publications, first diagnosis of the designated event 13 additional adjudicated cas CH-D and stroke from the CE trial were available for this a Statistical Analysis Age at menopause was defin age at which a woman last had strual bleeding, bilateral o tomy, or began using menop. mone therapy. For hyste without bilateral oophorecton at menopause was the age a woman either began using t ll Comparisons of outcomes are preeseachof sented as Hils and 95% Cls stratified lE + MPA by prior cardiovascular disease (denalysis. fined as history of myocardial infarction, angina, coronary or carotid revascularization, stroke, transient ed by the ischemic attack, or peripheral arterial any men- disease) and randomization status in ophorec- the Dietary Modification Trial. The ausal hor- stratified models allow for flexible rectomy (and possibly different) hazard funciy,tiheage tions between strata and hence more t which a accurately capture the effects of htrhormone mone therapy. Preliminary analyses DOrloaded fi-m wrtjoma cam at Nitiomtl Itslitaie of HthS, oit April 5. 2007 02007 Aaoefiai Medjsil Aasod.umii. All i5hti .rieod.
showed no striking differences in HRs across categories of age or years since menopause in women with and without prior cardiovascular disease, or in unadjusted models and models adjusted for baseline risk facios (race/ ethnicity, education, physical activity, prior hormone use, body mass index (calculated as weight in kilograms divided by height in meters squared], left ventricular hypertrophy by electrocardiographic criteria, current smoking, hypertension, treated diabetes, and treated high serum cholesterol level). Therefore, the results of unadjusted models for all women are presented. For consistency with the display of IiRs within categories of age or years since menopause, the estimated absolute excess risks were obtained by applying the HR in each category to the observed annualized incidence in the placebo group. The 95% Cls were calculated by bootstrap methods. Likelihood ratio tests were used to test for differences between the age categories and the categories for years since menopause. The primary analyses of this study were based on the 2 trials combined. Separate tests for trend were performed to examine differences in hormone effects across 3 preselected, coded categories of age (50-59, 60-69, 70-79 years) or years since menopause (< 10, 10-19, and Ž20) using Cox regression model interaction terms."i The tests siratified the baseline disease rates for the CEE and CEE + MPA cohorts by active vs placebo (4 strata), while leaving the form of the (marginal) HR for hormone therapy unspecified as a function of time from randomization. The marginal HR dependence on age or years since menopause also was unrestricted through the separate Iticlusion for each trial cohort of indicator variables for the upper 2 age group categories or years since menopause categories in the log HR models. The models included regression terms for interaction between cohorts and coded indicator variables for the 3 categories of age or years since menopause. The categories were assigned an 198 HORMONE TI IERAPY USE AND RISK OF CARDIOVASCULAR DISEASE ordinal number (1, 2, 3) and then the resulting variable was fitted as a continlous linear variable in the risk models. Interaction terms between age or years since menopause and active vs placebo groups tested whether there were differential effects of hormone therapy as a function of age or years since menopause These models allow the data for the 2 trials to be combined because they do not make assumptions about baseline risk or the overall treatment effect of hormone therapy in each of the trials. Analyses also were performed for each of the trials separately. The method used to test HR interactions differs slightly from that used in previous publications,' -'- in that age and years since menopause are modeled as coded rather than as continuous variables. Models using coded variables are likely to be less sensitive to the effects, of extreme values but may occasionally yield different results than the models using continuous variables. Other analyses were defined for the purposes of this study based on a priori considerations of biologic plausibilitv. These included analyses aimed at separating out the effects of age and years since menopause by including terms for both variables as well as an interaction term. Models allowing the HRs and baseline disease incidence to vary by risk factor status were used to directly compare the HRs between the 2 trials. Further analyses tested whether the trends in the effect of hormone therapy by age or years since menopause varied with several factors potentially related to hormone status (eg, prior hormone use (never, past, current]; oophorectomy; presence or absence of vasomotor symptoms [never, mild, moderate or severe] at baseline). Tests were performed by including appropriate additional product interaction terms (eg, 3-way interaction of vasomotor symptoms, age, and hormone therapy treatment effect). The possibility that interactions between age and years since menopause could vary by duration of hormone therapy was examined in models and included additional product teems for duration of therapy. Adherence-adjusted sensitivity analyses censored a woman's event history 6 months after becoming nonadherent (defined as taking
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S. HRG. 110-129 Bioidentica
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CONTENTS Page Opening Statement of
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2 The sale of bioidentical hormone
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4 ever, as Dr. Wartofsky points out
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6 with every stage of the disease:
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8 I am pleased to appear before thi
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10 When the trials began, many rese
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Women who began treatment more than
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14 One small trial using oral estra
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16 FDA is aware that a growing numb
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18 DEPARTMENT OF HEALTH & HUMAN SER
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20 safety and efficacy. However, as
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22 adulteration and misbranding pro
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24 The 2002 CPG reflects FDA's curr
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26 Equally concerning are claims by
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28 concerned about the use and mark
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30 Part I: Materials and Partnershi
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32 drugs, when the compounding of t
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34 Our staff identified 34 Web site
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1. Introduction 36 Chairman Kohl, R
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diet and fitness products. 5 For ex
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include "natural" progesterone crea
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42 unique to the computer age, such
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computer users to spam(ftuce.0ov -
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46 accuracy of advertising for heal
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48 Now, you have identified in your
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50 claim." Therefore, since the ter
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52 Such quality control problems ha
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54 Statement Before the U.S. <stron
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in the U.S., whereas WHI participan
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58 between science and hearsay and
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60 How can we determine whether bio
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62 doctors-are not getting the obje
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64 27. Writing Group for the PEPI T
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66 Dr. MANSON. Well, I think that m
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68 Statement of Leonard Wartofsky,
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70 in the WHI. In fact, no study as
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In summary, the Endocrine Society i
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74 The FDA also regulates aspects o
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Statement of Loyd V. Allen, Jr., Ph
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82 Senator SMITH. Dr. Allen, as I h
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84 Now, when you are talking about
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86 The only thing the WHI proved wa
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88 Testimony Of T.S. Wiley before t
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Confusion and Media Hype 90 Instead
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92 see a doctor tell a diabetic nea
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94 the only compelling reason to ta
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96 identical hormones synthesized f
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98 The world as we know it, from ba
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100 thereby experienced long period
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102 Bio-identical progesterone repl
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104 had reached optimum theoretical
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106 and the patient can be can reas
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108 Estradiol and Analytical Resear
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110 A controlled systematic pilot c
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112 of set doses. The Wiley Protoco
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114 I'd advocate for either Accredi
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116 D.C., and established a goal to
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118 If this legislation passes, fed
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first and second finger on the barr
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122 These products that have been s
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124 Bcl-2, survivin and variant CD4
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126 These are experiments by other
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128 cerebro-cellular inflammation c
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130 Years # women *1>0.5 8 *1+ 9 *2
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*Breast cancer 132 -57 y.o. recurre
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134 *Labor intense for patient and
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136 Senator SMITH. Thank you very m
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138 makes these hormones uniquely s
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140 tomize the Wiley Protocol by ra
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142 "natural," because all lead to
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144 maceutical commerce, often with
Page 149 and 150: 146 WHITE PAPER #1 DID YOU KNOW THA
Page 151 and 152: 148 WHITE PAPER #2 Pharmacy Compoun
Page 153 and 154: 150 bleeding of the bowel, locate t
Page 155 and 156: 152 compounding standards can be en
Page 157 and 158: 154 I. The FDA's definition of a "N
Page 159 and 160: 156 ORIIGINAL CONTrMIBTION JANMA-EX
Page 161 and 162: Initially, the design allowed women
Page 163 and 164: ards analyses," stratified by clini
Page 165 and 166: year). These 'drop-in" rates were a
Page 167 and 168: years of prior use, 11 vs 2; HR, 4.
Page 169 and 170: trogen plus progestin exposure. Clo
Page 171 and 172: 168 RISKS AND BENEFITS OF ESTROGEN
Page 173 and 174: EFFECTS OF POSTMENOPAUSAL ESTIROGEN
Page 175 and 176: EFFECTS OF POSTMENOPAUSAL ESTROGEN
Page 179 and 180: pEyECTS OF POSTMENOPAUSAL ESTROGEN
Page 185 and 186: 10000 isoor i I ea '° a wan 20-24
Page 187 and 188: ~SDt~rpa g~2~Q ~ !~fm~. b~e ~ ng jh
Page 189 and 190: Is associated with an Increased ris
Page 191 and 192: 188 Postmenopausal hormone therapy
Page 193 and 194: group (P= 04001), and In this subgr
Page 195 and 196: Treatmnent recommendations Based on
Page 197 and 198: 21.Grodsteln F. Manson JE, Colditz
Page 199: _ ORWIGNAL CONTIuBUTION 196 Postmen
Page 203 and 204: (214 cases; P for trend=.72): howev
Page 205 and 206: 202 HORMONE THERAPY USE AND RISK OF
Page 207 and 208: mal studies, and laboratory studies
Page 213 and 214: 210 ,lmcCII na: CLI I tr: tarty ver
Page 215 and 216: 212 ,mucmai rimi &ronos farty bstro
Page 217 and 218: 214 LntIucwu miau: rronos nary estr
Page 219 and 220: XVI. PNharmacy Licensure Requiremen
Page 221 and 222: XVI. Pharmacy Licensure Requirement
Page 223 and 224: 220 Roster of Board of Pharmacy Ece
Page 225 and 226: 050. 0l7404405400 Al-h. PeVbU 03283
Page 227 and 228: Conclusions * Age is a powerful ris
Page 229 and 230: Women's Health Initiative Trials of
Page 231 and 232: Hormone Therapy after WHI * Change
Page 233 and 234: Statement of the American Pharmacis
Page 235 and 236: 232 APhA Statement to the S
Page 243 and 244: 240 Written Testimony of Steven F.
Page 245 and 246: 242 STATEMENT OF DAVID G. ADAMS On
Page 247 and 248: 244 Report on State Laws and Regula
Page 249 and 250: 246 Only one state, Utah, requires
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248 5. Compounding Copies of FDA-Ap
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Bioidentical Hormones - U.S. Senate Special Committee on Aging

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