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J Am Coll Cardiol, 2002; 40:693-702
© 2002 by the American College of Cardiology Foundation
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CLINICAL STUDY: ANGIOTENSIN ANTAGONISM

Effect of long-term therapy with ramipril in high-risk women

Eva Lonn, MD, MSc, FACC*,*, Rosa Roccaforte, MD{dagger}, Qilong Yi, MSc{ddagger}, Gilles Dagenais, MSc, MD, FACC§, Peter Sleight, MD, DM, FACC||, Jackie Bosch, MSc*, Pamela Suhan, BSN, Mary Micks*, Jeffrey Probstfield, MD, FACC#, Victoria Bernstein, MD**, Salim Yusuf, MBBS, DPhil, FACC* HOPE Investigators

* Department of Medicine, Division of Cardiology and Population Health Institute, McMaster University, Hamilton, Ontario, Canada
{dagger} Fate Benefratelli Hospital, Milan, Italy
{ddagger} Princess Margaret Hospital, Toronto, Ontario, Canada
§ Quebec Heart Institute, Laval University, Ste-Foy, Quebec, Canada
|| John Radcliffe Hospital, Oxford University, Oxford, England, United Kingdom
Cleveland Clinic Foundation, CIeveland, Ohio, USA
# University of Washington, Seattle, Washington, USA
** Vancouver Hospital and Health Sciences Centre, Vancouver, British Columbia, Canada

Manuscript received February 12, 2002; revised manuscript received April 19, 2002, accepted May 7, 2002.

* Reprint requests and correspondence: Dr. Eva Lonn, Hamilton Health Sciences, General Site, 237 Barton Street East, Hamilton, Ontario, Canada L8L 2X2.
lonnem{at}mcmaster.ca


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We evaluated the effects of long-term therapy with the angiotensin-converting enzyme (ACE) inhibitor ramipril on major cardiovascular (CV) outcomes in high-risk women.

BACKGROUND: The effect of long-term ACE inhibitor therapy in high-risk women without heart failure and with preserved left ventricular (LV) systolic function has not been previously reported.

METHODS: The Heart Outcomes Prevention Evaluation (HOPE) trial is a large, randomized clinical trial that evaluated ramipril and vitamin E in high-risk patients. We present the preplanned analysis of the effects of ramipril in women in the HOPE study. The study randomized 2,480 women aged ≥55 years with vascular disease or diabetes and at least one additional CV risk factor and without heart failure or a known low LV ejection fraction to ramipril (10 mg/day) or placebo. The primary outcome was the composite of myocardial infarction, stroke or CV death. Average follow-up was 4.5 years.

RESULTS: Treatment with ramipril resulted in reduced primary end point rates (11.3% vs. 14.9% in the placebo arm; relative risk [RR] 0.77, 95% confidence interval [CI] 0.62 to 0.96; p = 0.019), fewer strokes (3.1% vs. 4.8%; RR 0.64, 95% CI 0.43 to 0.96; p = 0.029) and fewer CV deaths (4.2% vs. 6.9%; RR 0.62, 95% CI 0.44 to 0.88; p = 0.0068). There were trends toward reduced rates of myocardial infarction, heart failure and all-cause death. The beneficial effect of ramipril was similar in women and men.

CONCLUSIONS: Treatment with ramipril reduces the CV risk in high-risk women without heart failure and with preserved LV systolic function.

Abbreviations and Acronyms
  ACE
  angiotensin-converting enzyme
  AT1
  angiotensin II type 1 receptor
  CAD
  coronary artery disease
  CI
  confidence interval
  CV
  cardiovascular
  CVD
  cardiovascular disease
  HOPE
  Heart Outcomes Prevention Evaluation trial
  LV
  left ventricle
  MI
  myocardial infarction
  RR
  relative risk

Ischemic cardiovascular disease (CVD) is the leading cause of death and a significant cause of morbidity among women in industrialized countries (1). Most cardiovascular (CV) events occur in postmenopausal women. Given the increasing life expectancy of women and the rise in the prevalence of diabetes, hypertension and other risk factors in the elderly, it is expected that the burden of death and disability related to CVD in women will increase further. Therefore, it is important to identify preventive strategies that can decrease the risk of a broad range of CV events in women.

Women have been generally underrepresented in clinical trials of CVD (2,3), and the evaluation of CV therapies in women has been frequently based on subgroup analyses. Results of such subgroup analyses are subject to numerous potential sources of error (4). A major confusing issue has been the frequent attempt to interpret subgroup data in isolation, even in trials that included only relatively few women; thus, there was a lack of adequate power for such analyses.

Angiotensin-converting enzyme (ACE) inhibitors have been clearly shown to have a wide range of cardiac and vascular protective actions (5,6). Until recently, CV trials had evaluated the long-term use of ACE inhibitors primarily in patients with heart failure and/or asymptomatic left ventricular (LV) dysfunction, and these trials had generally enrolled relatively few women (7–11).

The Heart Outcomes Prevention Evaluation (HOPE) study, a large, multi-center, randomized trial, evaluated the effects of the ACE inhibitor ramipril and of vitamin E in high-risk patients without heart failure and with preserved LV function (12). The study specifically attempted to recruit a large number of women to have reasonable power to detect moderate and plausible differences separately in this subgroup. This report focuses on analyses of the effects of ramipril in the women enrolled in the HOPE trial.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
The analysis of the effects of ramipril on major CV events in the women enrolled in the HOPE trial was preplanned. The Data Safety and Monitoring Committee, the Writing Group and the Data Management and Statistical Centre for this study were fully independent of the study sponsors. Detailed descriptions of the HOPE study design have been published (12,13). A brief summary with emphasis on details relevant to the current report follows.

Study group.   The HOPE trial enrolled women and men at high risk of CV events. Patients were eligible if they were ≥55 years, had a history of CVD (coronary artery disease [CAD], stroke or peripheral artery disease) or diabetes in the presence of at least one additional CV risk factor (total cholesterol >5.2 mmol/l [200 mg/dl], high-density lipoprotein cholesterol ≤0.9 mmol/l [35 mg/dl], hypertension [defined as the use of medication[s] to treat high blood pressure or blood pressure >160 mm Hg systolic or >90 mm Hg diastolic at the time of recruitment], known microalbuminuria or current smoking). Exclusion criteria included history of congestive heart failure or a known low LV ejection fraction (<40%), uncontrolled hypertension, myocardial infarction (MI), unstable angina or stroke within one month before study enrollment, use of or intolerance to ACE inhibitors or vitamin E and other major life-threatening illnesses. We attempted to randomize a high proportion (~25% to 30%) of women. All study participants provided written informed consent and the study protocol was approved by the Research Ethics Board of each participating center.

Study design.   After an active run-in period on ramipril at 2.5 mg/day, study patients were randomized to ramipril titrated up to 10 mg/day or placebo and to 400 IU/day natural-source vitamin E (RRR-alpha-tocopherol acetate) or placebo, using a 2 x 2 factorial study design.

Follow-up and study outcomes.   After randomization, patients were evaluated at one month, six months and every six months thereafter. At each visit, data were collected on outcome events, compliance and side effects. At baseline, one month, two years and study end, additional data were obtained on the use of concomitant drugs, and blood pressure was measured. Average follow-up was 4.5 years.

The primary study outcome was the composite of MI, stroke or CV death. Each individual component of the primary outcome was analyzed separately. The specified secondary study outcomes were all-cause death, revascularization procedures, hospital admission for unstable angina or heart failure and complications related to diabetes. Other outcomes analyzed were worsening angina, cardiac arrest, heart failure (with or without hospital admission), unstable angina with electrocardiographic changes and the development of diabetes. Detailed definitions of these outcomes have been published (13).

Statistical analysis.   Statistical analyses were carried out using SAS version 6.02 (SAS Institute, Cary, North Carolina). We targeted the recruitment of ~2,500 women and predicted an annual primary event rate of 4% in the placebo arm. For an average follow-up of five years, the planned analysis of the effects of ramipril in women was anticipated to have >80% power to detect a treatment effect of 25%. The HOPE study was stopped early because of clear evidence of a benefit with ramipril (12). Because this is a subgroup analysis of the HOPE study, we first assessed the balance in the baseline characteristics between women and men, and we compared the overall outcomes, independent of treatment assignment, between women and men. The t test or chi-square test, as appropriate, was used to evaluate the balance in the baseline characteristics, and Cox proportional hazards models, unadjusted and adjusted for baseline imbalances, were used to compare outcomes in women and men. We then compared baseline characteristics in women in the ramipril and placebo groups and analyzed the effect of ramipril in women. All analyses of the effects of ramipril were done on an intention-to-treat basis. Cox proportional hazards models were fitted to examine the effect of ramipril on study outcomes. Observed slight imbalances in baseline characteristics between the placebo and ramipril groups were controlled by fitting multivariate Cox models. Because of the factorial design, all analyses of the effects of ramipril were stratified for randomization to vitamin E or placebo. The effect of ramipril in women versus men was compared using models with a ramipril–gender interaction term and confirmed using the Breslow-Day test for homogeneity of odds ratios. Subgroup analyses were conducted to evaluate the consistency of the effect of ramipril on the primary study outcome among predefined subsets of women. Kaplan-Meier curves were drawn to visually show the impact of treatment on the main study outcomes.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
The HOPE trial enrolled 2,545 women. Of these, 65 were randomized to a lower dose of ramipril (2.5 mg/day or placebo) as part of a substudy (14). Therefore, the main analysis of the ACE inhibitor effect in women is described for 2,480 patients. Inclusion of the additional 65 women randomized to the lower ramipril dose or placebo did not alter the study results.

Baseline characteristics and outcomes in women and men.   At baseline, women were slightly older than men, had a higher systolic blood pressure and body mass index and were more likely to have a history of peripheral artery disease, hypertension, diabetes and hypercholesterolemia (Table 1). Men were more likely to have a history of CAD, previous MI, stable and unstable angina and previous revascularization procedures. Men had worse outcomes than women, both in the unadjusted analysis and after adjusting for baseline differences (Table 2).


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  		Table 1 Baseline Characteristics of the HOPE Study Women and Men

 

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  		Table 2 Primary, Secondary and Other Outcomes in Women and Men

 
Baseline characteristics and compliance of the HOPE study women by treatment assignment.   The baseline characteristics of the 2,480 women in the placebo and ramipril groups are shown in Table 3. Among the women randomly assigned to the ramipril group, 83.7% were taking ramipril at one year, 78.1% at two years, 76.6% at three years, 75.6% at four years and 73.8% at the study end. Among the women taking ramipril, the percentages of those who were receiving the full dose of 10 mg/day were 81.3% at one year, 68.6% at two years, 64.6% at three years, 55% at four years and 59.8% at the study end. Among the women who were randomly assigned to receive placebo, 88.8% were taking it at one year, 78.9% at two years, 74.6% at three years, 70.5% at four years and 68.1% at the end of the study. In addition, among women randomized to receive placebo, 3.4% were taking an open-label ACE inhibitor at one year, 6.8% at two years, 9.1% at three years, 11.1% at four years and 11.9% at the study end. Among causes for permanent study drug discontinuation, cough and angioedema were more common in women in the ramipril group and uncontrolled hypertension in those in the placebo group (Table 4). Women in the placebo group were more likely to use a nonstudy ACE inhibitor for blood pressure control (Table 4). More women than men required permanent discontinuation of active ramipril therapy because of cough (11.3% of women in the ramipril group vs. 2.2% of women in the placebo group, compared with 5.7% of men in the ramipril group vs. 1.7% of men in the placebo group).


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  		Table 3 Baseline Characteristics of Women in the Placebo and Ramipril Groups

 

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  		Table 4 Reasons for Discontinuation of Study Drug in the HOPE Study Women

 
Blood pressure.   Baseline and subsequent blood pressure measurements in the HOPE study women are shown in Table 5. The mean systolic and diastolic blood pressure change over the duration of the study was –0.6 ± 15.7 and –0.9 ± 8.6 mm Hg in the placebo group and –3.6 ± 16.5 and –2.4 ± 9.1 mm Hg in the ramipril group, respectively.


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  		Table 5 Blood Pressure at Baseline and at Follow-Up in the HOPE Study Women

 
Outcomes by treatment assignment.   The primary, secondary and other outcomes by treatment assignment to ramipril versus placebo are summarized in Table 6 and Figure 1. The women in the ramipril arm of the study had significantly fewer primary outcome events, deaths from CV causes, strokes and episodes of worsening angina. The beneficial effect of ramipril remained statistically significant after adjusting for the observed slight baseline imbalances between the women in the two treatment arms (no baseline imbalances between the treatment arms were noted in men). A strong trend toward a reduction in the risk of all-cause death was also noted; a total of 118 women (9.2%) in the ramipril group died, compared with 139 women (11.6%) in the placebo group (p [adjusted] = 0.08). There were also trends toward a reduced risk of MI, revascularization, heart failure, cardiac arrest and a new diagnosis of diabetes.


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  		Table 6 Effect of Ramipril on Primary, Secondary and Other Study Outcomes in Women and Men

 




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  		Figure 1 Kaplan-Meier estimates for the major cardiovascular (CV) outcomes and all-cause death in women and men in the ramipril and placebo groups.

 
Comparison of ramipril effects in women versus men.   There were no statistically significant differences in the effect of ramipril on any of the primary, secondary or other study outcomes in women versus men, both in the unadjusted analysis and after adjusting for baseline imbalances and other predictors of risk (Table 6).

Subgroup analysis.   The consistency of the results in key, clinically relevant predefined subgroups of women is shown in Figure 2. Although some subgroups had relatively few patients and few outcomes of interest, there were statistically significant benefits or trends toward beneficial effects of ramipril in all subgroups analyzed.



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  		Figure 2 The effects of ramipril on the primary study outcome in key subgroups of women. The data show the consistency of the benefit of ramipril. The dotted line represents the average treatment effect in women. The size of each box is proportional to the number of patients in each individual analysis. The p value is for the subgroup–ramipril interaction term in the Cox proportional hazards model. Similar results were obtained using the test for homogeneity of odds ratios in subgroups. CAD = coronary artery disease; CVD = cardiovascular disease; DM = diabetes mellitus; HRT = hormone replacement therapy; MI = myocardial infarction; PAD = peripheral arterial disease; RR = relative risk; TIA = transient ischemic attack.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Treatment with ramipril significantly reduced the risk of major vascular events in women. There was a 23% reduction in the risk of nonfatal MI, stroke or CV death, a 38% reduction in the risk of CV death and a 36% reduction in the risk of stroke. The risk of worsening angina was also significantly reduced. Similar trends were noted for other CV outcomes, including MI, total mortality and the development of heart failure. The beneficial effect of ACE inhibitor therapy occurred in a wide range of middle-aged and elderly postmenopausal women with a high prevalence of risk factors, including a history of hypertension present in 60.3% at baseline, diabetes in 53.3%, hypercholesterolemia in 71% and current smoking in 14%, and most of whom had a history of vascular disease. The benefits noted were additive to other medications with known cardioprotective effects and/or known to favorably modify coronary risk factors; these medications included beta-blockers administered at baseline in 34% of women in the HOPE trial, aspirin or other antiplatelet drugs in 64%, cholesterol-lowering drugs in 30% (this increased to 50% by the study end), diuretics in 25% and calcium channel blockers in 48%.

Similar to the overall HOPE study results, the magnitude of the benefit on major clinical outcomes in women appeared to exceed the small reduction in blood pressure attained (3 mm Hg systolic/1.5 mm Hg diastolic) and is likely to be related to a wide range of cardiac and vascular protective actions of long-term ACE inhibitor therapy, in addition to blood pressure lowering (5,6).

Previous clinical trials of long-term ACE inhibitor therapy have been conducted in women and men with hypertension and/or a low LV ejection fraction, with or without previous MI and with or without heart failure. Based on subgroup analyses in some of these trials, such as the Survival And Ventricular Enlargement (SAVE) study, which enrolled only 390 women, it was suggested that ACE inhibitors may be less effective in women than in men (15,16). In our study, we found no heterogeneity of effects by gender. The effects of ramipril appeared to be similar in women and in men, and this lack of gender-based difference was noted after controlling for baseline differences and other predictors of risk between women and men. We therefore believe that previous suggestions of possible lesser efficacy of ACE inhibitors in women are related to the low power of subgroup analyses in studies that included only a small number of women. A meta-analysis of the long-term ACE inhibitor trials in patients with a low ejection fraction also suggests no significant heterogeneity of effects by gender (17).

In our study, we noted an overall worse prognosis in men versus women, and we believe that this is related to the baseline differences in our study group, which included fewer women with a history of CAD and a history of MI.

Experimental studies have shown that estrogen deficiency is associated with increased angiotensin II type 1 (AT1) receptor gene expression, leading to enhanced biologic effects of the renin-angiotensin system, and it was suggested that this may partly explain the increased CV risk in postmenopausal women (18). Some, but not all, experimental studies have shown that estrogen causes downregulation of the vascular AT1 receptor and thus may lead to decreased oxidative stress, improved endothelial function and decreased CV risk (18–20). Estrogen administration in postmenopausal women may also reduce circulating ACE levels and suppress renin (21,22). However, estrogen was also shown to increase angiotensin II levels (23). Based on the complex interaction between estrogen and the renin-angiotensin system, a potentially differential effect of ACE inhibitors in postmenopausal women on estrogen replacement therapy versus those not receiving estrogen has been suggested (22). In our study, ramipril benefited both postmenopausal women receiving and those not receiving hormone replacement therapy. However, the number of women receiving hormone replacement therapy was small, and results of this subgroup analysis have to be regarded as purely exploratory.

Conclusions.   Our study provides strong evidence for the role of ACE inhibitor therapy in postmenopausal women at high risk of CV events, including those with established coronary, cerebrovascular or peripheral arterial disease and with diabetes and additional CV risk factors. This therapy significantly reduced the risk of major vascular events, CV death, stroke and worsening angina; the benefits were noted in addition to other protective agents, such as antiplatelet agents, beta-blockers and lipid-lowering drugs. The magnitude of benefit attained with long-term ACE inhibitor therapy in this middle-aged and elderly population at high risk of CV events appears to be similar in women and in men. Therefore, high-risk postmenopausal women should consistently be treated with ACE inhibitors, and this recommendation needs to be widely incorporated into clinical guidelines.


   Footnotes
 
The study was supported by the Medical Research Council of Canada, Hoechst-Marion-Roussel, AstraZeneca, King Pharmaceuticals, Natural Source Vitamin E Association and Negma.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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