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Hormone therapy and risk of all-cause mortality in women treated with statins.

B erglind et al are to be commended for their important and timely contribution to hormone therapy (HT) and cardiovascular disease (CVD) outcomes and mortality in statin-treated women. Although this study has limitations attributable to a national registryYbased cohort study, it included a broad range of women aged 40 to 74 years who were using statin therapy for primary and secondary prevention of CVD, with excellent representation of the general population. The results of this study are consistent with the prevailing literature and contribute to our current understanding of HT and statin therapy for the prevention of coronary heart disease (CHD) in women. In addition, this study lends further support for the progressive but unpopular position that combined HT and statin therapy may be the optimum option for reducing CHD and all-cause mortality in women. Media propagation of overinterpretation, misinterpretation, and overgeneralization of data has fueled misperceptions surrounding both HT and statin therapy for the prevention of CVD in women. The message of combined HT and statin therapy for the primary and secondary prevention of CHD in women has received little attention. The perception that statins reduce CHD in women in primary prevention is neither supported by data from primary prevention trials actually conducted in women nor supported by meta-analyses that included data derived solely from women in primary prevention. Expected treatment responses in women are, however, erroneously extrapolated from results in men. Meta-analyses that included data derived from men and women and a mixture of primary prevention and secondary prevention trial data are commonly referenced as supportive data for the use of statin therapy in the primary prevention of CHD in women. Furthermore, the perception that statin therapy reduces all-cause mortality in women in primary prevention or even in secondary prevention lacks evidence. On the other hand, randomized trials show that statin therapy reduces CHD when used for secondary prevention. The perception surrounding HT and CHD prevention has been similarly confusing for women and healthcare providers alike. In primary prevention, the data support a reduction in CHD and all-cause mortality when HT is initiated in young postmenopausal women at or near the time of menopause. On the other hand, HT has a null effect on CHD and all-cause mortality when initiated in women distant from menopause. In secondary prevention, the Heart and Estrogen/progestin Replacement Study showed an overall null effect of HT on CHD. However, within this null effect was a very interesting pattern of an early increase in myocardial infarction (MI) within the first year of HT initiation and primarily within the first 6 months and then a statistically significant reduction of CHD relative to placebo during the remaining 4-year intervention period. The likely explanation for this unique effect is that HT induced MI through rupture of susceptible coronary artery plaques. Estrogen increases the expression of matrix metalloproteinases (MMPs), particularly MMP-9, which is critical for the pathway of plaque rupture. In confirmation of this explanation and relevant to the study by Berglind et al, a subgroup analysis of the Heart and Estrogen/progestin Replacement Study showed that women who were randomized to HT and self-selected statin therapy did not exhibit an increased risk of MI in the first year of HT relative to women who were randomized to HT and were not exposed to statins. Statins suppress MMP-9 expression as a major mechanism for preventing plaque rupture and MI, and the ability of statins to suppress MMP-9 expression induced by estrogen has been shown in endothelial and macrophage cell cultures pretreated with statins before estrogen exposure. The potential complementary effects on CVD and opposing effects on adverse outcomes position combination HT and statin therapy as potentially effective partners in preventing CHD, reducing all-cause mortality, and reducing each other’s adverse effects across the entire postmenopausal age range of women. As reviewed above, statins have the potential to reduce plaque rupture induced by HT in secondary prevention, whereas HT has the potential to reduce new-onset diabetes mellitus caused by statin therapy, a major adverse effect that particularly occurs in women, because HT has been shown to reduce new-onset diabetes mellitus in both primary prevention and secondary prevention trials. Statin therapy may also play a role in reducing the venous thromboembolism adverse effects of HT. As supported by the current study by Berglind et al, HT adds the reduction of all-cause mortality to statin therapy in primary and secondary prevention, although this finding would have been considerably strengthened with a comparative analysis of HT effects among statin nonusers. All-cause mortality rates from 1992-1996 to 2002-2006 have risen in women across 42.8% of US counties, whereas during the same period, all-cause mortality rates increased in men in only 3.4% of US counties. Single-line messaging only further complicates the complex issues of primary prevention of CHD and initiation of HT in older women and in