The semi-competing risk problem revisited.

Re: Postmenopausal Hormone Use and the Risk of Nephrolithiasis: Results From the Women's Health Initiative Hormone Therapy Trials

After clinical trials end, continued follow-up of the assembled cohort often is desirable for additional research. Factors influencing participants' decisions to consent to additional follow-up and how these shape posttrial cohorts have not been broadly studied. We examined how two re-enrollment campaigns and the passage of time altered features of the posttrial cohorts compared with the original Women's Health Initiative (WHI) Hormone Therapy clinical trials. We examined associations that markers of sociodemography, health, lifestyle, and on-trial experiences had with re-enrollment and contrasted the characteristics of successive posttrial cohorts with those of the original enrollees. The posttrial enrollment campaigns re-enrolled 81.1% and 82.5% of available women, respectively. Women who re-enrolled tended to have better health characteristics than those not re-enrolled. Compared to women of comparable age in the original cohort, women retained for the second posttrial follow-up less often had a history of cardiovascular disease (odds ratio (OR) = 0.36), hypertension (OR = 0.57), diabetes (OR = 0.59), or measured cognitive deficit (OR = 0.40). These women more often had graduated from high school (OR = 1.72) and had participated in other WHI trials (OR = 1.76). We have examined experience with creating follow-up cohorts from participants in a single study. Thus, our findings may not apply to other cohorts and protocols. Posttrial enrollment in follow-up studies can be successful; however, the characteristics of the resulting cohort may differ substantially from the originally assembled group of trial participants. Collection during the original trial of potential predictors of differential re-enrollment may strengthen interpretation of findings.

The aim of the study was to determine the effect of menopausal hormone therapy on incident hypertension in the two Women's Health Initiative hormone therapy trials and in extended postintervention follow-up. A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. This analysis includes the subsample of 18,015 women who did not report hypertension at baseline and were not taking antihypertensive medication. Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 5,994) or placebo (n = 5,679). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 3,108) or placebo (n = 3,234). The intervention lasted a median of 5.6 years in the CEE plus MPA trial and 7.2 years in the CEE-alone trial with 13 years of cumulative follow-up until September 30, 2010. The primary outcome for these analyses was self-report of a new diagnosis of hypertension and/or high blood pressure requiring treatment with medication. During the CEE and CEE plus MPA intervention phase, the rate of incident hypertension was 18% higher for intervention than for placebo (CEE: hazard ratio [HR], 1.18; 95% CI, 1.09-1.29; CEE plus MPA: HR, 1.18; 95% CI, 1.09-1.27). This effect dissipated postintervention in both trials (CEE: HR, 1.06; 95% CI, 0.94-1.20; CEE plus MPA: HR, 1.02; 95% CI, 0.94-1.10). CEE (0.625 mg/d) administered orally, with or without MPA, is associated with an increased risk of hypertension in older postmenopausal women. Whether lower doses, different estrogen formulations, or transdermal route of administration offer lower risks warrant further study.

BackgroundThe putative effects of postmenopausal hormone therapy on the association between particulate matter (PM) air pollution and venous thromboembolism (VTE) have not been assessed in a randomized trial of hormone therapy, despite its widespread use among postmenopausal women.ObjectiveIn this study, we examined whether hormone therapy modifies the association of PM with VTE risk.MethodsPostmenopausal women 50–79 years of age (n = 26,450) who did not have a history of VTE and who were not taking anticoagulants were enrolled in the Women’s Health Initiative Hormone Therapy trials at 40 geographically diverse U.S. clinical centers. The women were randomized to treatment with estrogen versus placebo (E trial) or to estrogen plus progestin versus placebo (E + P trial). We used age-stratified Cox proportional hazard models to examine the association between time to incident, centrally adjudicated VTE, and daily mean PM concentrations spatially interpolated at geocoded addresses of the participants and averaged over 1, 7, 30, and 365 days.ResultsDuring the follow-up period (mean, 7.7 years), 508 participants (2.0%) had VTEs at a rate of 2.6 events per 1,000 person-years. Unadjusted and covariate-adjusted VTE risk was not associated with concentrations of PM < 2.5 μm (PM2.5) or < 10 μm (PM10)] in aerodynamic diameter and PM × active treatment interactions were not statistically significant (p > 0.05) regardless of PM averaging period, either before or after combining data from both trials [e.g., combined trial-adjusted hazard ratios (95% confidence intervals) per 10 μg/m3 increase in annual mean PM2.5 and PM10, were 0.93 (0.54–1.60) and 1.05 (0.72–1.53), respectively]. Findings were insensitive to alternative exposure metrics, outcome definitions, time scales, analytic methods, and censoring dates.ConclusionsIn contrast to prior research, our findings provide little evidence of an association between short-term or long-term PM exposure and VTE, or clinically important modification by randomized exposure to exogenous estrogens among postmenopausal women.

Evaluation of: Robinson JG, Wallace R, Limacher M et al.: Cardiovascular risk in women with non-specific chest pain (from the Women's Health Initiative hormone trials). Am. J. Cardiol. 102(6), 693–699 (2008). Chest pain is common, and often a specific cause fails to be diagnosed. There is particular concern that many women with a diagnosis of nonspecific chest pain (NSCP) may have atypical indications of coronary artery disease. Analysis of data from the Women's Health Initiative hormone therapy trials, amongst 24,834 postmenopausal women aged 50–79 years who were initially free of cardiovascular disease, found that NSCP was associated with a 139% (95% CI: 46–292%) increase in the risk of subsequent angina. Similar proportional increases in risk were found for cardiac surgery or interventions and nonfatal myocardial infarction. Thus, a diagnosis of NSCP in a woman, using current technology, does not rule out the possibility of increased coronary risk. It would be prudent to treat women with NSCP as being at a higher than average risk of cardiovascular disease

Mediation analysis is important for understanding the mechanisms whereby one variable causes changes in another. Measurement error could obscure the ability of the potential mediator to explain such changes. This article focuses on developing correction methods for measurement error in the mediator with failure time outcomes. We consider a broad definition of measurement error, including technical error, and error associated with temporal variation. The underlying model with the "true" mediator is assumed to be of the Cox proportional hazards model form. The induced hazard ratio for the observed mediator no longer has a simple form independent of the baseline hazard function, due to the conditioning event. We propose a mean-variance regression calibration approach and a follow-up time regression calibration approach, to approximate the partial likelihood for the induced hazard function. Both methods demonstrate value in assessing mediation effects in simulation studies. These methods are generalized to multiple biomarkers and to both case-cohort and nested case-control sampling designs. We apply these correction methods to the Women's Health Initiative hormone therapy trials to understand the mediation effect of several serum sex hormone measures on the relationship between postmenopausal hormone therapy and breast cancer risk.

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; In the Women's Health Initiative Hormone Trials (WHI-HT), breast cancer risk was increased with estrogen plus progestin (E+P) but not with unopposed estrogen (E-alone). We hypothesized that E+P would preferentially metabolize to 16α-hydroxyestrone (16α-OHE1) rather than 2-hydroxyestrone (2-OHE1), and that breast cancer risk would be associated with baseline and 1 year changes in estrogen metabolites: positively for 16α-OHE1 levels and negatively for levels of 2-OHE-1 and the 2:16 ratio.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; In a prospective case-control study nested in the WHI-HT, 845 confirmed breast cancer cases were matched to 1,690 controls by age and ethnicity. Using stored serum, 2-OHE1 and 16α-OHE1 levels were measured by enzyme immunoassay at baseline, and for those randomized to active treatment (&lt;i&gt;n&lt;/i&gt; = 1,259), at 1 year.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; The 1-year increase in 16α-OHE1 was greater with E+P than E-alone (median 55.5 pg/mL vs. 43.5 pg/mL, &lt;i&gt;P&lt;/i&gt; &lt; 0.001), but both increased 2-OHE1 by ∼300 pg/mL. Breast cancer risk was modestly associated with higher baseline levels of 2-OHE1 and the 2:16 ratio, and for estrogen receptor+/progesterone+ cases only, higher baseline 16α-OHE1 levels. For those randomized to active treatment, breast cancer risk was associated with greater increase in 2-OHE-1 and the 2:16 ratio, but associations were not significant.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Although E+P modestly increased 16α-OHE1 more than E-alone, increase in 16α-OHE1 was not associated with breast cancer.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Impact:&lt;/b&gt; Study results do not explain differences between the WHI E+P and WHI E-alone breast cancer results but metabolism of oral HT, which may explain smaller than expected increase in breast cancer compared with endogenous estrogens. &lt;i&gt;Cancer Epidemiol Biomarkers Prev; 21(11); 2022–32. ©2012 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

Education, Income, and Incident Heart Failure in Post-Menopausal Women: The Women's Health Initiative Hormone Therapy Trials

In the Women's Health Initiative Hormone Trials (WHI-HT), breast cancer risk was increased with estrogen plus progestin (E+P) but not with unopposed estrogen (E-alone). We hypothesized that E+P would preferentially metabolize to 16α-hydroxyestrone (16α-OHE1) rather than 2-hydroxyestrone (2-OHE1), and that breast cancer risk would be associated with baseline and 1 year changes in estrogen metabolites: positively for 16α-OHE1 levels and negatively for levels of 2-OHE-1 and the 2:16 ratio. In a prospective case-control study nested in the WHI-HT, 845 confirmed breast cancer cases were matched to 1,690 controls by age and ethnicity. Using stored serum, 2-OHE1 and 16α-OHE1 levels were measured by enzyme immunoassay at baseline, and for those randomized to active treatment (n = 1,259), at 1 year. The 1-year increase in 16α-OHE1 was greater with E+P than E-alone (median 55.5 pg/mL vs. 43.5 pg/mL, P < 0.001), but both increased 2-OHE1 by ∼300 pg/mL. Breast cancer risk was modestly associated with higher baseline levels of 2-OHE1 and the 2:16 ratio, and for estrogen receptor+/progesterone+ cases only, higher baseline 16α-OHE1 levels. For those randomized to active treatment, breast cancer risk was associated with greater increase in 2-OHE-1 and the 2:16 ratio, but associations were not significant. Although E+P modestly increased 16α-OHE1 more than E-alone, increase in 16α-OHE1 was not associated with breast cancer. Study results do not explain differences between the WHI E+P and WHI E-alone breast cancer results but metabolism of oral HT, which may explain smaller than expected increase in breast cancer compared with endogenous estrogens.

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; In the Women's Health Initiative Hormone Trials (WHI-HT), breast cancer risk was increased with estrogen plus progestin (E+P) but not with unopposed estrogen (E-alone). We hypothesized that E+P would preferentially metabolize to 16α-hydroxyestrone (16α-OHE1) rather than 2-hydroxyestrone (2-OHE1), and that breast cancer risk would be associated with baseline and 1 year changes in estrogen metabolites: positively for 16α-OHE1 levels and negatively for levels of 2-OHE-1 and the 2:16 ratio.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; In a prospective case-control study nested in the WHI-HT, 845 confirmed breast cancer cases were matched to 1,690 controls by age and ethnicity. Using stored serum, 2-OHE1 and 16α-OHE1 levels were measured by enzyme immunoassay at baseline, and for those randomized to active treatment (&lt;i&gt;n&lt;/i&gt; = 1,259), at 1 year.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; The 1-year increase in 16α-OHE1 was greater with E+P than E-alone (median 55.5 pg/mL vs. 43.5 pg/mL, &lt;i&gt;P&lt;/i&gt; &lt; 0.001), but both increased 2-OHE1 by ∼300 pg/mL. Breast cancer risk was modestly associated with higher baseline levels of 2-OHE1 and the 2:16 ratio, and for estrogen receptor+/progesterone+ cases only, higher baseline 16α-OHE1 levels. For those randomized to active treatment, breast cancer risk was associated with greater increase in 2-OHE-1 and the 2:16 ratio, but associations were not significant.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Although E+P modestly increased 16α-OHE1 more than E-alone, increase in 16α-OHE1 was not associated with breast cancer.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Impact:&lt;/b&gt; Study results do not explain differences between the WHI E+P and WHI E-alone breast cancer results but metabolism of oral HT, which may explain smaller than expected increase in breast cancer compared with endogenous estrogens. &lt;i&gt;Cancer Epidemiol Biomarkers Prev; 21(11); 2022–32. ©2012 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

To examine the opinions of obstetrician-gynecologists regarding hormone therapy (HT) and the results from the Women's Health Initiative (WHI). Separate surveys were sent to two groups of practicing obstetrician-gynecologists: (1) respondents to a 2004-2005 survey (follow-up 1) and (2) members of the American College of Obstetricians and Gynecologists' Collaborative Ambulatory Research Network (follow-up 2 CARN). These studies complete a longitudinal study investigating obstetrician-gynecologists' opinions of the evidence from WHI. Response rates were 64.5% and 58.8%, respectively. Responses from both surveys were generally consistent with the results from the 2004-2005 survey. A majority of physicians from both survey populations were skeptical of the combined HT results. Respondents were more likely to find the results of the unopposed estrogen trial convincing. Similar to the results from the 2004-2005 study, CARN physicians generally disagreed with the decision to end the WHI trials. Unlike the 2004-2005 study, there was no consistent effect of either age or year that residency was completed on physician opinions. Similar to the 2004-2005 study, physicians who considered alternative therapies as viable treatment options were more likely to report that they found the trial results convincing. The results from follow-up 2 CARN indicate that physicians in the south were most likely and physicians in the east were least likely to prescribe HT, suggesting that unmeasured sociocultural parameters might influence HT prescribing practice. Obstetrician-gynecologists remain generally skeptical of the WHI results, although less so of the estrogen-only trial. The early end to the trials may have contributed to their skepticism.

Earlier findings from the Women's Health Initiative hormone therapy trials, which enrolled women aged 50 to 79, are well known. Now, investigators have

Blood Pressure Variability and Heart Failure Hospitalization: Results From the Women's Health Initiative

The Women's Health Initiative (WHI) postmenopausal hormone therapy (HT) trials were designed to determine the balance of benefits and risks of HT taken for chronic disease prevention by initially healthy postmenopausal women (age range, 50—79 years; mean age, 63 years). Women with an intact uterus were randomized to estrogen–progestin or placebo for a mean of 5.6 years; women with hysterectomy were randomized to estrogen alone or placebo for a mean of 7.1 years. Compared with their respective placebo‐group counterparts, women in the estrogen–progestin group were significantly more likely to experience an adverse health event, whereas women in the estrogen‐alone group were as likely to do so. Specifically, estrogen–progestin was associated with increased risks of coronary heart disease (CHD), stroke, venous thromboembolism, and breast cancer, as well as reduced risks of hip fracture and colorectal cancer. Estrogen alone was associated with an increased risk of stroke and a reduced risk of hip fracture; it had no effect on CHD risk. The results do not support the use of HT for chronic disease prevention in postmenopausal women as a whole. However, because few WHI participants were within 5 years of menopause, these trials cannot conclusively determine the risk–benefit balance of HT in recently menopausal women. Accumulating data suggest that the timing of HT initiation in relation to age or menopause onset may critically influence the relationship between such therapy and risk of CHD as well as its overall risk–benefit balance, with younger or recently menopausal women experiencing more favorable effects than older women or women further from menopause.

The Women's Health Initiative (WHI) postmenopausal hormone therapy (HT) trials were designed to determine the balance of benefits and risks of HT taken for chronic disease prevention by initially healthy postmenopausal women (age range, 50—79 years; mean age, 63 years). Women with an intact uterus were randomized to estrogen–progestin or placebo for a mean of 5.6 years; women with hysterectomy were randomized to estrogen alone or placebo for a mean of 7.1 years. Compared with their respective placebo‐group counterparts, women in the estrogen–progestin group were significantly more likely to experience an adverse health event, whereas women in the estrogen‐alone group were as likely to do so. Specifically, estrogen–progestin was associated with increased risks of coronary heart disease (CHD), stroke, venous thromboembolism, and breast cancer, as well as reduced risks of hip fracture and colorectal cancer. Estrogen alone was associated with an increased risk of stroke and a reduced risk of hip fracture; it had no effect on CHD risk. The results do not support the use of HT for chronic disease prevention in postmenopausal women as a whole. However, because few WHI participants were within 5 years of menopause, these trials cannot conclusively determine the risk–benefit balance of HT in recently menopausal women. Accumulating data suggest that the timing of HT initiation in relation to age or menopause onset may critically influence the relationship between such therapy and risk of CHD as well as its overall risk–benefit balance, with younger or recently menopausal women experiencing more favorable effects than older women or women further from menopause.