presents a description of the 2,304 WHISCA participants at the time of their enrollment in the WHI. Although there were differences in the characteristics of women between trials with respect to many factors, within both trials randomization provided good balance between active intervention and placebo. describes follow-up. Of the original cohort, 1933 (84%) women consented to and attended at least one post-trial cognitive assessment. With respect to the factors in and compared to those who did not participate in post-trial follow-up, these women at WHI enrollment tended to be younger, non-smokers, free of diabetes or cardiovascular disease, and prior users of oral contraceptives and to have higher 3MS scores (all p<0.05). Post-trial participation rates were similar between women assigned to active versus placebo therapy (p=0.21). Among women from the WHI CEE+MPA trial, the average (standard deviation) on-trial pre-WHISCA, on-trial WHISCA, and post-trial follow-ups were 3.0 (0.7), 2.6 (0.9), and 4.0 (1.3) years. Among women from the WHI CEE-Alone trial, these averages were 3.0 (0.7), 3.6 (0.4), and 2.4 (1.1) years. None of these averages differed significantly between women assigned to active versus placebo therapy (all p>0.10).
Characteristics of participants at the time of enrollment into the WHI by treatment assignment: frequency and (percent).
Follow-up during WHISCA and the WHISCA Extension
provides a comparison of the on-trial and post-trial mean test scores and the estimated relative treatment effects for each standardized domain score, with mean effect sizes expressed in terms of standard deviation units. During the trials, CEE-based therapies were associated with a mean (standard error) relative decrement in global cognition of 0.073 (0.027) SD units; during post-trial follow-up, this relative decrement was 0.070 (0.025) SD units and the average relative decrement across the full span of follow-up was 0.071 (0.025) SD units. Each of these decrements in global cognitive function was statistically significant p≤0.01 and the on-trial and post-trial mean decrements were of similar magnitudes (p=0.89). portrays the fitted mean global cognitive function scores collected during WHISCA follow-up. In this cohort, relative decrements occurred, on average, 3-4 years from WHI enrollment and were maintained across time. Note that the termination of the CCE+MPA trial occurred an average of 5.6 (1.0) years from WHI enrollment and the termination of the CEE-Alone trial occurred an average of 6.6 (0.6) years from WHI enrollment for these women. As indicated in the figure, 6 years from randomization only 32% of the measurements occurred during the trial and in later years, almost all occurred after the termination of the trials.
Table 2 Mean on-trial, post-trial, and overall test scores and, expressed in standard deviation units, relative domain-specific treatment effects ([unk]active minus placebo): adjustment for baseline 3MS score, trial (CEE+MPA vs CEE-Alone), time since WHISCA enrollment, (more ...)
Figure 2a Fitted mean (with 95% confidence intervals) standardized global cognition test scores over time from women grouped by WHI treatment assignment with adjustment for baseline 3MS score, trial (CEE+MPA vs CEE-Alone), age, education, race/ethnicity, smoking (more ...)
There was a mean on-trial relative decrement for each domain-specific cognitive function; these reached statistical significance (p≤0.05) for verbal knowledge, verbal fluency, figural memory, and fine motor speed. The magnitudes of effect sizes were uniformly smaller during the post-trial and none were significant on their own, however on-trial and post-trial decrements differ significantly only for verbal fluency (p=0.009). portrays the pattern over time of the means for verbal fluency, for which the initial relative decrement, which was apparent as early as Year 1, dissipated from 6 years on during follow-up.
Figure 2b Fitted mean (with 95% confidence intervals) standardized verbal fluency test scores from women grouped by WHI treatment assignment with adjustment for baseline 3MS score, trial (CEE+MPA vs CEE-Alone), age, education, race/ethnicity, smoking status, body (more ...)
There was little difference in the relative effects of CEE+MPA versus CEE on global cognitive function, both during on-trial and post-trial follow-up (). For three domains, however, there was some evidence of differences between the two drug regimens. For figural memory (p=0.05), spatial ability (p=0.04), and fine motor speed (p=0.01), the on-trial decrements appeared to be limited to CEE therapy and were not apparent for CEE+MPA therapy. For the spatial ability, the differences in the effect sizes between regimens persisted into the post-trial follow-up (p=0.01).
Table 3 Mean on-trial, post-trial, and overall relative treatment effects: adjustment for baseline 3MS score, trial (CEE+MPA vs CEE-Alone), time since WHISCA enrollment, age, education, race/ethnicity, smoking status, body mass index, hypertension, alcohol intake, (more ...)