Lower Risk for Gallbladder Disease With Transdermal Hormone Therapy
Lower Risk for Gallbladder Disease With Transdermal Hormone Therapy
Liu B, Beral V, Balkwill A, Green J, Sweetland S, Reeves G, for the Million Women Study Collaborators. Gallbladder disease and use of transdermal versus oral hormone replacement therapy in postmenopausal women: prospective cohort study. BMJ 2008 July 10[Epub ahead of print].
Hormone therapy (HT) increases risk for gallbladder disease, but there is less risk with transdermal HT than with oral HT, report collaborators from the prospective Million Women Study (MWS) conducted in Scotland and England. The study included 1.3 million postmenopausal women, aged 50 to 69 years (mean age, 56 y), recruited from the National Health Service (NHS) breast screening clinics from 1996 to 2001 and followed using their unique NHS number to link to hospital admission data for gallbladder disease. The intent of the study was to determine whether transdermal HT reduces risk of gallbladder disease in postmenopausal women compared with women who use oral HT. Main outcome measures were the adjusted relative risk (RR) and standardized incidence rates of hospitalization for gallbladder disease or cholecystectomy according to use of HT.
Compared with never users of HT, current and past users had an increased RR of gallbladder disease, which was significantly greater in current users (1.64; 95% confidence interval [CI], 1.58-1.59) than in past users (1.27; 95% CI, 1.22-1.32; P < 0.001). Risk for current users differed significantly by delivery method, with a substantially lower risk of gallbladder disease seen with transdermal compared with oral HT (RR 1.17; 95% CI, 1.10-1.24 vs RR 1.74; 95% CI, 1.68-1.80; P < 0.001). In addition, women using equine estrogens had a higher risk of gallbladder disease than those using estradiol (RR 1.79; 1.72-1.87 vs RR 1.62; 95% CI, 1.54-1.70; P < 0.001). Among users of oral HT, higher dosages conferred greater risk. RR did not change with adjustment for potential confounders. Use of transdermal rather than oral HT over 5 years could avoid one cholecystectomy in 140 users, the study reports.
Oral HT increases women's risk of gallbladder hospitalizations and procedures -- about this, there is little to debate. This report by Liu et al from the MWS is welcome news for all of us eager to learn more about the risks and benefits of alternative formulations of HT compared to oral conjugated estrogens (CE). From the epidemiologic perspective, this report is superb. The very large sample size, linkage to healthcare records for ascertainment of gallbladder events, completeness of follow-up, stability of HT exposure, ability to adjust for many possible confounding variables, and the prospective design provide the strongest evidence possible from an observational study. In the Women's Health Initiative (WHI), CE increased the risk of gallbladder events with hazard ratios (HR) of 1.67 for estrogen alone and 1.59 for estrogen plus progestin. The striking similarity of those trial findings to the current RR of 1.64 for oral CE in the MWS inspires confidence in this thorough analysis of other aspects of HT exposure: method of administration, dose, current versus past use, time since stopping, CE versus estradiol, and combinations with various progestogens. The findings provide reassurance that transdermal estradiol confers much less risk of gallbladder disease than oral HT preparations.
Many of the comparisons in this report are highly statistically significant due to the sample size and availability of more than 6 million women-years of follow-up. Some of the significant findings are small in magnitude and less clinically important. For example, the RR for oral estradiol is not impressively lower than for CE. Women considering taking oral preparations should be counseled about an increased risk of gallbladder disease, whether their prescription contains estradiol or CE. High doses of HT confer greater risk, but this report unfortunately does not inform us as to the risk of low-dose oral therapy because doses less than the standard 0.625 mg were not separated out. As in the WHI, combination HT therapy with progestin did not appear to affect the hazard ratios for HT. The findings were consistent across many subgroups. The only exception was that HR seemed to diminish in magnitude among women as body mass index (BMI) increased. The most likely explanation for this apparent interaction is a statistical phenomenon. Heavier women have higher rates of gallbladder events in the absence of HT exposure. Thus, for the HR to be identical across categories of BMI, the rate of gallbladder events in the women taking HT has to achieve greater and greater heights in the higher BMI groups. In comparison, a twofold risk of gallbladder events can occur with rates that are quite a bit lower in the thinner women. As the authors note, the absolute rates of gallbladder events and the rate differences do not diminish in the overweight and obese groups. Thus, clinicians should counsel women taking oral HT about an increased risk of gallbladder events regardless of their BMI.
Reports like this are crucial if we are to learn how the risks and benefits of HT differ for the many agents that will never be tested in randomized trials large enough to detect differences in clinical safety endpoints. We cannot just assume that transdermal methods of administration are safer than oral HT. In the absence of evidence to the contrary, it is prudent to assume that other HT formulations have similar risks and benefits to the oral agents tested in large trials. However, the evidence provided in this report and others like it can be used to fill in the blanks left by the trials, so that women can make informed decisions about whether and how to use HT.
From the NAMS First to Know e-newsletter released September 17, 2008
For more, please visit http://www.menopause.org/news.aspx
Summary
Liu B, Beral V, Balkwill A, Green J, Sweetland S, Reeves G, for the Million Women Study Collaborators. Gallbladder disease and use of transdermal versus oral hormone replacement therapy in postmenopausal women: prospective cohort study. BMJ 2008 July 10[Epub ahead of print].
Hormone therapy (HT) increases risk for gallbladder disease, but there is less risk with transdermal HT than with oral HT, report collaborators from the prospective Million Women Study (MWS) conducted in Scotland and England. The study included 1.3 million postmenopausal women, aged 50 to 69 years (mean age, 56 y), recruited from the National Health Service (NHS) breast screening clinics from 1996 to 2001 and followed using their unique NHS number to link to hospital admission data for gallbladder disease. The intent of the study was to determine whether transdermal HT reduces risk of gallbladder disease in postmenopausal women compared with women who use oral HT. Main outcome measures were the adjusted relative risk (RR) and standardized incidence rates of hospitalization for gallbladder disease or cholecystectomy according to use of HT.
Compared with never users of HT, current and past users had an increased RR of gallbladder disease, which was significantly greater in current users (1.64; 95% confidence interval [CI], 1.58-1.59) than in past users (1.27; 95% CI, 1.22-1.32; P < 0.001). Risk for current users differed significantly by delivery method, with a substantially lower risk of gallbladder disease seen with transdermal compared with oral HT (RR 1.17; 95% CI, 1.10-1.24 vs RR 1.74; 95% CI, 1.68-1.80; P < 0.001). In addition, women using equine estrogens had a higher risk of gallbladder disease than those using estradiol (RR 1.79; 1.72-1.87 vs RR 1.62; 95% CI, 1.54-1.70; P < 0.001). Among users of oral HT, higher dosages conferred greater risk. RR did not change with adjustment for potential confounders. Use of transdermal rather than oral HT over 5 years could avoid one cholecystectomy in 140 users, the study reports.
Commentary by Andrea Z. LaCroix, PhD
Oral HT increases women's risk of gallbladder hospitalizations and procedures -- about this, there is little to debate. This report by Liu et al from the MWS is welcome news for all of us eager to learn more about the risks and benefits of alternative formulations of HT compared to oral conjugated estrogens (CE). From the epidemiologic perspective, this report is superb. The very large sample size, linkage to healthcare records for ascertainment of gallbladder events, completeness of follow-up, stability of HT exposure, ability to adjust for many possible confounding variables, and the prospective design provide the strongest evidence possible from an observational study. In the Women's Health Initiative (WHI), CE increased the risk of gallbladder events with hazard ratios (HR) of 1.67 for estrogen alone and 1.59 for estrogen plus progestin. The striking similarity of those trial findings to the current RR of 1.64 for oral CE in the MWS inspires confidence in this thorough analysis of other aspects of HT exposure: method of administration, dose, current versus past use, time since stopping, CE versus estradiol, and combinations with various progestogens. The findings provide reassurance that transdermal estradiol confers much less risk of gallbladder disease than oral HT preparations.
Many of the comparisons in this report are highly statistically significant due to the sample size and availability of more than 6 million women-years of follow-up. Some of the significant findings are small in magnitude and less clinically important. For example, the RR for oral estradiol is not impressively lower than for CE. Women considering taking oral preparations should be counseled about an increased risk of gallbladder disease, whether their prescription contains estradiol or CE. High doses of HT confer greater risk, but this report unfortunately does not inform us as to the risk of low-dose oral therapy because doses less than the standard 0.625 mg were not separated out. As in the WHI, combination HT therapy with progestin did not appear to affect the hazard ratios for HT. The findings were consistent across many subgroups. The only exception was that HR seemed to diminish in magnitude among women as body mass index (BMI) increased. The most likely explanation for this apparent interaction is a statistical phenomenon. Heavier women have higher rates of gallbladder events in the absence of HT exposure. Thus, for the HR to be identical across categories of BMI, the rate of gallbladder events in the women taking HT has to achieve greater and greater heights in the higher BMI groups. In comparison, a twofold risk of gallbladder events can occur with rates that are quite a bit lower in the thinner women. As the authors note, the absolute rates of gallbladder events and the rate differences do not diminish in the overweight and obese groups. Thus, clinicians should counsel women taking oral HT about an increased risk of gallbladder events regardless of their BMI.
Reports like this are crucial if we are to learn how the risks and benefits of HT differ for the many agents that will never be tested in randomized trials large enough to detect differences in clinical safety endpoints. We cannot just assume that transdermal methods of administration are safer than oral HT. In the absence of evidence to the contrary, it is prudent to assume that other HT formulations have similar risks and benefits to the oral agents tested in large trials. However, the evidence provided in this report and others like it can be used to fill in the blanks left by the trials, so that women can make informed decisions about whether and how to use HT.
From the NAMS First to Know e-newsletter released September 17, 2008
For more, please visit http://www.menopause.org/news.aspx