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(Circulation. 2002;105:2962.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Statin Therapy, Cardiovascular Events, and Total Mortality in the Heart and Estrogen/Progestin Replacement Study (HERS)

David M. Herrington, MD, MHS; Eric Vittinghoff, PhD; Feng Lin, MS; Josephine Fong, MS; Fran Harris, MS; Donald Hunninghake, MD; Vera Bittner, MD; Helmut G. Schrott, MD; Roger S. Blumenthal, MD; Robert Levy, MD, for the HERS Study Group

From the Department of Internal Medicine/Cardiology (D.M.H.), Wake Forest University School of Medicine, Winston-Salem, NC; the Department of Epidemiology and Biostatistics (E.V., F.L., J.F., F.H.), University of California-San Francisco, San Francisco; the Departments of Pharmacology and Medicine/Cardiology (D.H.), University of Minnesota Health Center, Minneapolis; the Department of Medicine (V.B.), University of Alabama at Birmingham, Birmingham; the Department of Preventive Medicine (H.G.S.), University of Iowa College of Medicine, Iowa City; the Preventive Cardiology Center (R.S.B.), Johns Hopkins Hospital, Baltimore, Md; and Wyeth-Ayerst Research (R.L.), Radnor, Pa.

Correspondence to David M. Herrington, MD, MHS, Department of Internal Medicine/Cardiology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157. E-mail dherring{at}wfubmc.edu

	Abstract

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Background— Although effects of statins on cardiovascular outcomes are well established in men, fewer data exist for women. Furthermore, the effects of statins plus hormone replacement therapy (HRT) on cardiovascular outcomes are uncertain.

Methods and Results— We examined statin use, cardiovascular events, and total mortality in the Heart and Estrogen/progestin Replacement Study (HERS), a randomized clinical trial of estrogen plus progestin versus placebo in postmenopausal women with heart disease (n=2763). A nonrandomized comparison of statin users and nonusers revealed lower rates of the primary outcome, nonfatal myocardial infarction or coronary heart disease death (relative hazard [RH]=0.79, 95% confidence intervals [CI] 0.63 to 0.99, P=0.04), and total mortality (RH=0.67, 95% CI 0.51 to 0.87, P=0.003). Rates of venous thromboembolic events were also lower among statin users (RH=0.45, 95% CI 0.23 to 0.88, P=0.02). HRT resulted in a significant increase in early risk for primary events in women who did not use statins (RH=1.75, 95% CI 1.02 to 3.03, P=0.04) but not in statin users (RH=1.34, 95% CI 0.63 to 2.86, P=0.45). Adjustment for postrandomization statin use showed no effect of HRT on risk for the primary outcome (RH=0.96, 95% CI 0.77 to 1.29; P=0.72).

Conclusions— In HERS, statin use was associated with lower rates of cardiovascular events, venous thromboembolic events, and total mortality. These data provide strong support for statin use in eligible women with coronary disease.

Key Words: coronary disease • hormones • lipids • risk factors • women

	Introduction

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Optimal treatment of coronary heart disease (CHD) in women remains an important goal, especially in postmenopausal women with established disease—a group at high risk for cardiovascular events and death.¹ Although the effects of statins on cardiovascular events are well established in men, the effects in women are less certain. The major secondary prevention trials of statin therapy included relatively few women (<20% in each trial), and the observed risk reductions in women varied widely.^2–4 No trial has shown statins to have a significant effect on total mortality in women.

There are also few data regarding the interaction of statins and postmenopausal hormone replacement therapy (HRT) for cardiovascular risk reduction. Several lines of evidence suggest that HRT might be more effective in statin users. In small, short-term trials^5–7 and observational studies,^8,9 women using statins plus HRT had lower low-density lipoprotein (LDL) cholesterol and higher high-density lipoprotein (HDL) cholesterol than women using either therapy alone. The ability of statins to lower C-reactive protein¹⁰ also may offset the adverse effect of HRT. Despite these promising observations, previous studies were not designed to determine the combined effect of statins and HRT on cardiovascular events. Finally, the debate continues about whether excess statin use in the placebo group might have contributed to the overall null effect in the Heart and Estrogen/progestin Replacement Study (HERS).

To clarify the effects of statins on prevention of recurrent cardiovascular events and total mortality in women, and to examine the impact of concurrent statin use on cardiovascular effects of HRT, we analyzed data from HERS.

	Methods

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The HERS design and main results have been described previously.^11–13 Briefly, 2763 postmenopausal women (mean age 66.7 years) with CHD were randomized to receive either 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate in one daily pill (n=1380) or placebo (n=1383) and were monitored, on average, for 4.1 years (range 3.6 to 5.3 years). The primary outcome was death from CHD or nonfatal myocardial infarction (MI). Secondary outcomes included unstable angina, coronary revascularization procedures, stroke or transient ischemic events, venous thromboembolic events (VTEs), and all-cause mortality.

Clinic staff determined concurrent medication use by inspecting current prescription bottles. Women on nonstatin forms of lipid-lowering therapy at baseline (n=292) were excluded from all analyses. Effects of individual statins (lovastatin, simvastatin, pravastatin, or fluvastatin) were not compared because of the small numbers in each subgroup.

Statistical Analyses
Univariate associations between baseline variables and statin use were evaluated by use of the ² test for categorical variables and t tests for continuous variables. Cox proportional hazard models were used to examine the relation between statin use and the risk for clinical cardiovascular events while adjusting for baseline variables nominally associated with the primary outcome, including race, diabetes (according to self-report or fasting glucose 125 mg/dL), hypertension (systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg), creatinine clearance <40 mL/min, LDL cholesterol, HDL cholesterol, prior MI, and congestive heart failure (New York Heart Association class I to III). Separate models adjusted for variables nominally associated with statin use produced similar patterns of results (data not shown). Cox models were also constructed to estimate the adjusted relative hazard (RH) for any statin use during the trial or stratified by duration of statin use, including years of use before randomization. In these models, statin use was treated as a time-dependent variable. In all models, events that occurred after statin therapy began were attributed to statins even if the woman subsequently stopped using them. In other, less conservative models, events were attributed to statin use only after varying periods of time on statins (lead time lag) and no longer attributed to statins after varying periods of time off them (trailing lag); however, these results did not substantially alter inferences about statin use and clinical events (data not shown).

	Results

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Statin Use
In HERS, 1004 women (36.3%) used statins at baseline and 426 (11.3%) were using other forms of lipid-lowering medication; this was not significantly different between the two treatment groups.^12,14 During the trial, 708 women initiated statin therapy. This number included 497 women among the subset not using other forms of lipid-lowering therapy at baseline. New statin use was more common in the placebo than in the HRT group (385 versus 323, respectively, P=0.005).

Baseline statin users tended to be white, better educated, and healthier (fewer smokers, more exercise), with fewer comorbid conditions (diabetes, gallbladder disease) than nonusers. They were also more likely to take aspirin and calcium channel blockers and less likely to have had an MI (P<0.05 for each) (Table 1). However, statin users were also more likely to have undergone surgical or catheter-based coronary revascularization before randomization (P<0.05 for each). Similar patterns were observed in women who used statins at any time during the trial, compared with nonusers.

View this table: [in this window] [in a new window]   Table 1. Characteristics of HERS Participants (n=2763) According to Statin Use at Baseline (Study Entry)

Statin Use and Clinical Events
Women taking statins at baseline or at any time during the trial had significantly fewer primary CHD events (MI or CHD death) than did nonusers (Table 2). The RH for women who used statins for 3 years (duration of follow-up 5.7±2.4 years [mean±SD]) was 0.74 (95% CI 0.57 to 0.96, P=0.02), whereas the RH for those who used statins for <3 years was 0.89 (95% CI 0.64 to 1.23, P=0.48). Similar patterns of risk reduction were observed for MI and CHD death when considered separately; however, differences between statin users and nonusers were not statistically significant. In contrast, rates of unstable angina, revascularization, stroke, or transient ischemic attack were nearly identical in users and nonusers of statin therapy.

View this table: [in this window] [in a new window]   Table 2. CHD and Other Clinical Events According to Statin Use During the HERS Trial

All-cause mortality was significantly lower in any statin users (Table 2) and in women who had used statins for 3 years (RH=0.70, 95% CI 0.52 to 0.93, P=0.01). Risk reductions of roughly similar magnitude were observed for both cancer deaths and other deaths; however, these generally did not achieve statistical significance.

Rates of VTEs were also dramatically lower in statin users at baseline or at any time during follow-up (Table 2). Among women who used statins for 3 years, the RH for VTEs was 0.40 (95% CI 0.18 to 0.91, P=0.03). Despite the lower absolute rate of VTEs in statin users versus nonusers, the RH for VTEs associated with HRT remained elevated in both groups (statin users: HRT=4.13, placebo=0.48 events/1000 person-years, RH=8.64, 95% CI 1.08 to 69.1, P=0.04; nonusers: HRT=7.85, placebo=3.17 events/1000 person-years, RH=2.48, 95% CI 1.15 to 5.36, P=0.02).

Statin–HRT Interactions
Among women not on statins at baseline, HRT was associated with a 75% increase in risk for primary CHD events during the first year (RH=1.75, 95% CI 1.02 to 3.03, P=0.04). In contrast, among baseline statin users, the year-1 RH for HRT was diminished and not significantly different from unity (RH=1.34, 95% CI 0.63 to 2.86, P=0.45) (Figure 1B). The formal test for an interaction between HRT and statin use for year-1 events was not significant (P=0.57). Despite the difference in year-1 event rates, the overall RHs for HRT after 4.1 years of follow-up were nearly identical in statin users and nonusers (Table 3).

View larger version (13K): [in this window] [in a new window]   Figure 1. Cumulative incidence of primary events (nonfatal myocardial infarction and coronary heart disease deaths) according to baseline use of statin therapy and treatment assignment. A, Hormone therapy (solid line) versus placebo (dashed line) among women not on statins at baseline. B, Hormone therapy (solid line) versus placebo (dashed line) among baseline statin users.

View this table: [in this window] [in a new window]   Table 3. Primary CHD Events (MI and CHD Death) According to Statin Use at Baseline and After Randomization

Several subgroups according to statin use were examined to see if a beneficial effect of HRT was obscured by greater use of statins in the placebo group (Table 3). However, the RHs remained close to unity, even when analyses were limited to women whose statin use did not change during follow-up or women who never used statins during HERS. Similarly, results were unchanged when statin use was treated as a time-dependent covariate.

	Discussion

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The present study provides greater clarity concerning effects of statins in women with coronary disease. The results confirm a significantly reduced risk for recurrent cardiovascular events in women, while suggesting that the estimate of risk reduction falls between the most optimistic and the most pessimistic (and nonsignificant) estimates from previous studies. The present study also provides, for the first time, evidence that statins may lower total mortality in women. These results, plus the lower risk of VTEs in statin users and possible attenuation of an early adverse cardiovascular effect of HRT, provide substantial additional support for statin use in postmenopausal women with coronary disease. These analyses also show that the overall null effect of HRT in HERS was not due to excess statin use in the placebo arm.

Variability in effects among three previous randomized clinical trials of statin therapy for secondary prevention of cardiovascular disease produced uncertainty about statin effects in women. Despite significant reductions in risk with statin therapy in women in the Scandinavian Simvastatin Survival Study (4S) (n=827, relative risk [RR]=0.65, 95% CI=0.47 to 0.91, P=0.01)¹⁵ and the Cholesterol And Recurrent Events (CARE) trial (n=582, RR=0.57, 95% CI=0.34 to 0.96, P=0.035),² there was no significant risk reduction in the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study, the largest of the three (n=1516, RR=0.89, 95% CI=0.67 to 1.18).⁴ Variations in treatment effects cannot be attributed to differences in efficacy among various statins because the most divergent results are between CARE and LIPID, both of which used pravastatin. Variations in baseline risk, degree of lipid lowering, duration of follow-up, and other factors could account for some observed differences; however, the critical factor is likely the small number of women enrolled. In contrast, although the association between statin use and cardiovascular risk in HERS is based on nonrandomized comparisons, it is drawn from standardized prospective observations from a much larger number of women than in previous randomized trials (n=2763) (Figure 2).

View larger version (9K): [in this window] [in a new window]   Figure 2. Risk ratios and 95% CIs for cardiovascular events (MI or CHD death) associated with statin use in women enrolled in major secondary prevention trials of statin therapy and in HERS. Sizes of squares are proportional to numbers of women in each study.

Among the statin trials, only 4S published sex-specific rates of all-cause mortality.¹⁵ In 4S, despite a 34% reduction in major coronary events in women, statin therapy had no effect on total mortality (RH=1.16, 95% CI 0.68 to 1.99; P=0.58).^3,15 In contrast, statin users in HERS had a roughly 30% lower rate of total mortality. The significantly lower rates of total mortality in HERS resulted from similar reductions in CHD death and deaths from cancer and other causes. Fewer cancer deaths with statin use were also observed in the LIPID trial.⁴ These observations in HERS and LIPID are encouraging, because earlier data^16,17 suggested a possible increased risk for cancer with statin use. The nominally significant association between statin use and lower rates of noncardiac death is difficult to explain because no biologically plausible mechanism accounts for a favorable effect on the risk of death from these heterogeneous causes. Thus, the observed association between statin use and lower rates of total mortality in HERS should be interpreted cautiously.

Lower risk for VTEs in statin users was previously reported in HERS¹⁸ and from a large retrospective cohort analysis.¹⁹ Our work extends the original HERS report by providing absolute rates of VTEs in statin users and nonusers and by examining HRT effects on VTE risk in the setting of statin use. The relative increase in risk for VTEs with HRT is significantly elevated in statin users and nonusers. However, the impact of HRT on absolute risk is attenuated in statin users because their overall risk of having a VTE is lower. Thus, the rate of VTEs in women on HRT and statins was only slightly higher than in women who did not use statins and were on placebo (4.1/1000 person-years versus 3.2/1000 person-years). Statins may reduce risk for VTEs through anticoagulant effects on tissue factor expression, fibrinogen levels, or blood viscosity, and by promoting fibrinolytic activity through decreases in plasminogen activator inhibitor-1.²⁰

Lipid profiles are more favorable in women on both statins and HRT than in women on either treatment alone.^5,7 In HERS, however, there was no incremental risk reduction for cardiovascular events in women on both statins and HRT versus women on statins alone. However, the pattern of early increase in risk with HRT seemed attenuated among baseline statin users. HRT is associated with increased C-reactive protein,^21–23 an acute-phase reactant that is strongly and independently associated with cardiovascular risk.²⁴ Recently, Koh et al²⁵ documented that statin therapy attenuates the increase in C-reactive protein that occurs with oral estrogen therapy.

An excess of 62 new statin users in the placebo group could have biased the HERS results toward the null, yet excluding new or any statin users or adjusting for statin use revealed no underlying benefit of HRT. This is consistent with previous results^26,27 finding no benefit of estrogen on progression of established coronary atherosclerosis.

Because statin use in HERS was not randomized, we adjusted for differential distribution of other factors that could have influenced the risk for the primary outcome. However, some factors such as education or overall health status are complex variables, and the possibility of residual confounding remains. Furthermore, without details about specific drugs and the doses of statins used in HERS, comparison with trials of individual statins can only be qualitative. However, the many women in HERS, the systematic documentation of statin use, clinical events, and other covariates, and the concordance with results from women in the major secondary prevention trials of statins support the present findings.

In summary, rates of nonfatal MI, CHD death, VTEs, and total mortality were all significantly lower among statin users in HERS. Despite the potent effects of statins on risk for clinical events, differential use of statins between the two arms does not appear to explain the overall null effect of HRT in HERS. A suggestion that statins attenuate the early increased risk for cardiovascular events associated with HRT requires further confirmation. Taken together, these data provide strong support for statin use in women with coronary disease.

	Acknowledgments

 
This study was supported by Wyeth-Ayerst Research (Radnor, Pa). Research support and/or occasional honoraria were also received from AstraZeneca (Dr Hunninghake), Bristol-Myers Squibb (Drs Blumenthal and Hunninghake), Eli Lilly & Co (Drs Herrington and Bittner), Kos Pharmaceuticals (Dr Hunninghake), Merck & Co (Drs Bittner and Blumenthal), Novartis (Dr Blumenthal), and Pfizer, Inc (Drs Bittner, Schrott, Blumenthal, Herrington, and Hunninghake).

	Footnotes

 
Dr Herrington received research support, occasional honoraria, and consultant fees from Eli Lilly & Co, Pfizer, Inc, and Wyeth-Ayerst Research. Dr Hunninghake received research support and occasional honoraria from Astra Zeneca, Kos Pharmaceuticals, Merck & Co, and Pfizer, Inc, as well as research support from Bristol-Myers Squibb and Wyeth-Ayerst Research. Dr Bittner received research support and occasional honoraria from Merck & Co, Pfizer, Inc, and Eli Lilly & Co, as well as research support from Wyeth-Ayerst Research. Dr Blumenthal received clinical research support from Wyeth-Ayerst Research, Merck & Co, Bristol-Myers Squibb, Pfizer, Inc, and Novartis. Dr Schrott received research support and occasional honoraria from Pfizer, Inc, as well as research support from Wyeth-Ayerst Research.

Deceased.

Received January 8, 2002; revision received April 12, 2002; accepted April 12, 2002.

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