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European Journal of Heart Failure 2007 9(6-7):602-609; doi:10.1016/j.ejheart.2007.02.001
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© 2007 European Society of Cardiology

Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure — A population study

Marie Hudsona,*,1, Elham Rahmea, Hassan Behloulia, Richard Sheppardb and Louise Pilotea,1

a Division of Clinical Epidemiology, The Research Institute of the McGill University Health Centre, 1650 Cedar Ave, Montreal (QC), Canada H3G 1A4
b Division of Cardiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

* Corresponding author. Tel: +1 514 934 1934x44163; fax: +1 514 934 8293. E-mail address: marie.hudson{at}mcgill.ca


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been shown to improve survival in patients with congestive heart failure (CHF). We wish to determine whether there are sex-related differences in the optimal treatment of congestive heart failure.

Methods: Using administrative databases, all patients > >=65 years of age discharged with a diagnosis of CHF between January 1998 and March 2003 and who filled a prescription for an ARB or an ACE inhibitor within 90 days of discharge were identified. Time to all-cause death in women and men on ACE inhibitors or ARBs was compared.

Results: There were 10,223 women (8627 ACE inhibitors and 1596 ARBs) and 9475 men (8484 ACE inhibitors and 991 ARBs). Hypertension was more common in women (50.1%) than men (33.1%). Women on ARBs had better survival than those on ACE inhibitors (adjusted hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.59, 0.80). There was no difference in survival in men prescribed ARBs compared to ACE inhibitors (HR 1.10, 95% CI 0.95, 1.30).

Conclusion: These sex differences in treatment-related outcome are important but should be confirmed in a randomized trial before ARBs are preferentially prescribed to women with CHF.

Key Words: Angiotensin receptor blockers • Angiotensin converting enzyme inhibitors • Congestive heart failure • Sex differences

Received March 20, 2006; Revised November 27, 2006; Accepted February 5, 2007


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Congestive heart failure (CHF) is an important public health problem. It affects almost 5 million Americans [1]. Between 1970 and 2002, hospital discharges for CHF in the United States rose by 157%, with women having a greater rate of increase. In 2002, there were 529,000 CHF discharges for women compared to 441,000 for men. In addition, women accounted for 62.5% of the total CHF mortality compared to 37.5% in men.

The aetiology of CHF differs between the sexes, with hypertension playing a greater role in women and ischaemic heart disease a greater role in men [2]. There may also be genetic differences between men and women with CHF. In particular, a new gene in the angiotensin converting enzyme (ACE) family, the ACE2 gene, has been identified and shown to map to defined quantitative trait loci on the X chromosome [3,4]. However, little is known about whether there are differences in the optimal treatment of CHF between men and women.

Angiotensin II plays a major role in the pathophysiology of CHF and has become one of the targets of choice for the treatment of CHF. Several large clinical trials have clearly shown that ACE inhibitors [5] and angiotensin receptor blockers (ARBs) [6] improve survival in patients with CHF compared to placebo. In a head-to-head comparison, the improvement in survival in patients with CHF was comparable between losartan, an ARB, and captopril, an ACE inhibitor [7]. In a subgroup analysis, the results were similar in women and men. However, the groups were relatively small and the results were not statistically significant.

The Gender and Sex Determinants of Cardiovascular Disease (GENESIS) Team is a group of basic science, clinical, epidemiological and health services researchers investigating the sex and gender determinants for the development, presentation, process of care and outcome of cardiovascular disease where "gender" determinants are behavioural and environmental factors and "sex" determinants are biological and genetic factors (www.epimgh.mcgill.ca/GENESIS). Given the differences in women and men with CHF noted above and as part of the GENESIS program of research, we hypothesized that there could be sex-related differences in the effectiveness of ACE inhibitors and ARBs in women and men with CHF. We therefore undertook this population-based study to test this hypothesis.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study group and data sources
We used the administrative database that stores the information on hospital discharge summaries for the province of Quebec (Maintenance et Exploitation des Données pour l'Étude de la Clientèle Hospitalière [Med-Echo]) to create a cohort of patients 65 years of age or older who were hospitalized for CHF. Patients were identified on the basis of a discharge diagnosis of CHF (International Classification of Diseases, Ninth Revision, code 428) between January 1998 and March 2003. The reliability of the coding diagnosis for CHF in administrative databases has been shown to be high [8,9]. This CHF cohort [10] has been used in other pharmaco-epidemiologic studies.

Using encrypted Medicare numbers, we then linked this cohort with the physician and drug claims database for the province of Quebec (the Régie de l'Assurance Maladie du Québec [RAMQ]). This latter database contains information on all outpatient prescriptions for patients 65 years of age or older as well as all inpatient and outpatient diagnostic and therapeutic procedures in Quebec. It provides survival status for more than 99% of patients. It has been validated for the accuracy of prescription claims [11].

2.2. Demographic, clinical, and hospital characteristics
Baseline demographic information are available from the above-mentioned databases. As many as 15 secondary diagnoses can be included in the hospital discharge summary database; these secondary diagnoses were used to obtain data about patient comorbid conditions at baseline. Cardiac medications that may influence survival after CHF were identified. Finally, we obtained information on the specialty of the treating physician (3 categories [cardiologist, internist, or general practitioner and others]), as well as on the following characteristics of the hospital in which the CHF was treated: annual CHF volume (low volume <31, medium volume >31 and <121 and high volume >121 admissions for CHF/year), and with or without a university affiliation. These variables, as defined in administrative databases, have been shown to be predictors of mortality in CHF [12].

2.3. Prescription groups
We identified patients who filled at least one prescription for an ARB or an ACE inhibitor within 90 days of discharge. This time frame was used to include patients who may not have filled their prescriptions immediately despite receiving them at discharge. Patients who switched from an ACE inhibitor to an ARB, or vice versa, were included in the analysis in the group corresponding to their first prescription and were censored at the time of switch. Patients who filled prescriptions for both ACE inhibitors and ARBs concomitantly were excluded from the analysis.

We calculated daily dosages based on each patient's first prescription and created three dosage categories: no drug, below target dose, or at- or above-target dose. The target dose of each drug was identified from randomized, controlled trials. For ACE inhibitors, the target doses were as follows: ramipril 10 mg/d, enalapril 20 mg/d, lisinopril 35 mg/d, fosinopril 40 mg/d, captopril 150 mg/d, quinapril 40 mg/d, perindopril 4 mg/d and cilazapril 2.5 mg/d. For ARBs, target doses were as follows: losartan 50 mg/d, valsartan 320 mg/d, candesartan 32 mg/d, irbesartan 150 mg/d, telmisartan 80 mg/d and eprosartan 800 mg/d.

We calculated several measures to determine the extent to which patients followed their treatment regimens. Among patients with discharge prescriptions, we calculated the proportion of patients who filled at least 1 prescription during the period 275 to 365 days (that is, 9 to 12 months) after discharge. In addition, we calculated the proportion of time for which a patient was covered by prescriptions during the first year after discharge or the proportion of time until death if the patient died earlier. These measures were calculated on the basis of a variable indicating the duration of each filled prescription available in the drug claims database. We also calculated the proportion of patients who had a prescription for 80% or more of the time during the first year of follow up.

2.4. Outcomes
The main outcome was time to all-cause death in men and women dispensed an ACE inhibitor or an ARB.

2.5. Statistical analysis
We compared demographic, clinical, physician and hospital characteristics according to sex and according to whether patients were dispensed an ARB or an ACE inhibitor.

Unadjusted mortality was compared among women and men prescribed ACE inhibitors or ARBs after discharge from their admission for CHF. Kaplan-Meier curves were generated and results were compared using the log-rank test.

To account for differences in follow up and to control for differences among patients, multivariable Cox proportional hazards modelling was used. In all models, we adjusted for the following fixed variables: age, comorbidities at baseline (hypertension, diabetes, cerebrovascular disease, renal failure, chronic obstructive pulmonary disease, atrial fibrillation, myocardial infarction, peripheral vascular disease, malignancy, liver disease, dementia, rheumatological disease), cardiac procedures at baseline (coronary angiography, percutaneous coronary intervention, coronary artery bypass grafting), other discharge medications (β-blockers, diuretics, hydralazine, nitrates, digoxin, clopidogrel, warfarin, amiodarone, sotalol, calcium channel blockers and statins), year of CHF (to account for temporal trends), physician specialty (cardiologist, internist or general practitioner), hospital characteristics (CHF volume and university affiliation), time to first prescription and length of stay.

In the adjusted analyses, we also used two binary time-dependent exposure variables, one to identify periods of exposure and the other dose. The variable for exposure indicated current exposure by assigning a value of one to all periods during which the patient had a filled prescription and zero to other periods. The variable for dose assigned the value of one to those periods when the current dosage was at or above the target dosage and the value of zero to periods when dosage was below that.

Since we found important differences between the baseline rates of hypertension between women and men and because hypertension is known to underlie CHF more often in women than in men [2], we were concerned about the possible effect modification between the class of drug and the presence or absence of hypertension. We therefore further stratified our analysis by hypertension, present or not.

There were a total of 46 covariates included in the main models. Thus, applying a Bonferroni correction for multiple testing, p<0.001 would be considered statistically significant.

All statistical analyses were performed by using the SAS (version 8) statistical software package (SAS Institute Inc., Cary, North Carolina).

2.6. Ethical considerations
There were minimal risks to the subjects observed in this study. All the data used for study analyses were anonymous and confidential. All personal identifiers were scrambled by the provincial government agencies before we received the data. All results are presented in summary form only. The study was approved by the McGill University Ethics Review Board.

2.7. Role of the funding source
This study was funded by grants from the Canadian Institutes of Health Research and the Heart and Stroke Foundation. The funding sources had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, and in the preparation, review, or approval of the manuscript. The authors had full and unique access to the data for the study.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The cohort consisted of 19,698 patients with an admission for CHF between January 1998 and March 2003 who filled a prescription for an ARB (N=2587 {13.1%}) or an ACE inhibitor (N=17,111 {86.9%}) within 90 days of discharge. Of these, 105 patients (0.5%) filled a prescription for an ACE inhibitor and an ARB on the same day and were excluded from the analysis. In women, 8627 received an ACE inhibitor and 1596 an ARB whereas in men 8484 received an ACE inhibitor and 991 an ARB (Table 1). Women had a diagnosis of hypertension more commonly than men (47% versus 32%, respectively) whereas men had a diagnosis of myocardial infarction more commonly than women (26% versus 20%, respectively). Men also had diagnoses of renal disease and chronic obstructive pulmonary disease more often than women. Women were prescribed beta-blockers, calcium channel blockers, diuretics and nitrates at discharge more often than men. This is consistent with the higher rates of hypertension present in women. On average, general practitioners used ACE inhibitors more often than ARBs and cardiologists used ARBs more often than ACE inhibitors. Other demographic, clinical, physician and hospital characteristics were fairly similar between women and men and are presented in Table 1. During follow up, 2258 patients switched from an ACE inhibitor to an ARB and 464 from an ARB to an ACE inhibitor. Overall, patients were followed for an average of 2-3 years after they were dispensed their first prescription.


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  		Table 1 Characteristics of patients with congestive heart failure who filled prescriptions for ACE inhibitors or ARBs

 
3.1. Prescription characteristics
Prescription patterns for the study drugs are presented in Table 2. Of note, the time to first prescription was slightly longer for ARBs than ACE inhibitors and more patients were dispensed target doses of ARBs than ACE inhibitors. We adjusted for these differences in the analysis. Overall one-year persistency rates to either ACE inhibitors or ARBs were low, with 18-29% of patients being non-persistent within the first year of treatment, depending on which measure was used. Women had generally similar rates of persistency compared to men. Interestingly though, the pattern of persistency by sex and drug went in opposite directions. Thus, women were generally less persistent to ACE inhibitors than to ARBs whereas men were more persistent with ACE inhibitors than with ARBs.


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  		Table 2 Prescription patterns for patients prescribed ACE inhibitors or ARBs after an admission for congestive heart failure according to sex

 
3.2. Outcomes after congestive heart failure
In unadjusted analysis, women prescribed ARBs had better survival than those prescribed ACE inhibitors (log-rank test p=0.001) and men prescribed ACE inhibitors had better survival compared to those prescribed ARBs (log-rank test p=0.015) (Fig. 1). After adjustment for current exposure, dose and other potentially confounding variables, the survival advantage of ARBs over ACE inhibitors persisted in women (HR 0.69, 95% CI 0.59, 0.80, p<0.0001). However, there was no difference in survival in men prescribed an ARB compared to those prescribed an ACE inhibitor (HR 1.10, 95% CI 0.95, 1.30, p=0.21). As could be expected, in the adjusted models, there were several independent predictors of death, including age (women HR 1.04 (95% CI 1.03, 1.04, p<0.0001) and men HR 1.03 (95% CI 1.03, 1.04, p<0.0001)) and renal disease (women HR 1.31 (95% CI 1.21, 1.42, p<0.0001) and men HR 1.22 (95% CI 1.13, 1.31, p<0.0001)).


Figure 01
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  		Fig. 1 Unadjusted Kaplan-Meier curves for women and men prescribed an ARB or an ACE inhibitor within 90 days of discharge from an admission for congestive heart failure.

 
Since there were more hypertensive women than men in our cohort, the question arose whether the improved survival seen in women on ARBs compared to ACE inhibitors could be a marker for better blood pressure control or whether there was a difference in the effect of the two classes of drugs independent of hypertension. The analysis was therefore further stratified by the presence or absence of hypertension. In women, the survival advantage of ARBs over ACE inhibitors was present whether the patients were hypertensive or not (HR 0.65, 95% CI 0.52, 0.80, p<0.0001 in hypertensive women and HR 0.72, 95% CI 0.59, 0.90, p<0.002 in non-hypertensive women). Unlike what was found in the overall analysis in men, ARBs were comparable to ACE inhibitors in hypertensive men (HR 0.86, 95% CI 0.64, 1.15, p not significant) but were associated with worse survival compared to ACE inhibitors in non-hypertensive men (HR 1.20, 95% CI 1.01, 1.43, p<0.03) (Fig. 2). Thus, the improved survival with ARBs compared to ACE inhibitors in women is present independently of hypertension. In addition, ACE inhibitors appear to be superior to ARBs in hypertensive men with CHF.


Figure 02
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  		Fig. 2 Adjusted hazard ratios and 95% confidence intervals of survival in patients with CHF dispensed prescriptions for ARBs compared to ACE inhibitors according to sex and the presence or absence of hypertension.

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In this population-based cohort of almost 20,000 elderly women and men with CHF, we found that ARBs were associated with a significantly improved survival compared to ACE inhibitors in all women, whether hypertensive or not. We also found that survival with ARBs was comparable to ACE inhibitors in hypertensive men but that ACE inhibitors appeared to be associated with better survival in non-hypertensive men. Of note, sex specific differences in persistency to ACE inhibitors and ARBs were noted and, in particular, women appeared to be more persistent to ARBs than to ACE inhibitors. Thus, our data suggest that ARBs should be the drug of choice in women.

There is good evidence from CHARM-Alternative [13] in patients with CHF and VALIANT [14] in patients after acute myocardial infarction to show that ARBs are a good alternative in patients who cannot tolerate an ACE inhibitor. Furthermore, CHARM-Added [15] showed that ARBs in addition to ACE inhibitors reduce cardiovascular mortality in patients with CHF and Val-HeFT [16] and VALIANT [14] showed that the combination reduced hospital admissions for worsening heart failure in patients with CHF and after acute myocardial infarction, respectively. However, studies comparing ACE inhibitors to ARBs have failed to show that ARBs are superior to ACE inhibitors. In CHF, the initial ELITE study [17] found that losartan was associated with better survival than captopril (risk reduction in all-cause mortality comparing losartan to captopril 46%, 95% confidence interval 5 to 69%, p=0.035). However, mortality was neither a primary nor a secondary endpoint in ELITE. In the RESOLVD [18] study, there was a trend towards better survival with enalapril compared to candesartan (20/327 (6.1%) deaths in the candesartan group compared to 4/109 (3.7%) in the enalapril group, odds ratio 1.71, 95% confidence interval 0.57, 5.12). ELITE II [7], the largest study to date comparing ACE inhibitors and ARBs in CHF using mortality as the primary endpoint, found that the two classes of drugs were similar in their reduction of mortality (hazard ratio comparing losartan to captopril 1.13, 95% confidence interval 0.95, 1.35). The findings of ELITE II were recently confirmed in a large meta-analysis comparing ARBs to ACE inhibitors (odds ratio for all-cause mortality 1.06, 95% confidence interval 0.90, 1.26) [6]. Similarly, two studies comparing an ARB to an ACE inhibitor after acute myocardial infarction failed to show superiority of the ARB. The OTIMAAL trial [19] compared losartan to captopril in patients after an acute myocardial infarction with signs and symptoms of CHF and/or left ventricular dysfunction and found that, after a mean follow up of 2.7 years, mortality in the losartan group was comparable to that in the captopril group (relative risk with losartan 1.13, 95% CI 0.99, 1.28). The VALIANT trial [14] compared valsartan to captopril in patients after an acute myocardial infarction complicated by left ventricular dysfunction and/or heart failure and found, after a median follow up of 24.7 months, that the mortality in the two groups was similar (hazard ratio for valsartan 1.00, 97.5% CI 0.90, 1.11).

There is very little data on the relative benefits of each class of drugs in women compared to men. In ELITE II, there was no difference in the subgroups of women (hazard ratio 1.14) and men (hazard ratio 1.12), although the groups were small (967 women and 2185 men) and the confidence intervals crossed the null in both groups.

Our data are consistent with those of the randomized trials. Indeed, in unadjusted analysis simply comparing all patients on ACE inhibitors or ARBs, we found no significant difference in survival (data not shown). However, our population is different from that of the clinical trials and includes many patients who may not otherwise meet the rigid inclusion criteria of randomized trials. In this sense, it has greater generalizability. Secondly, our study involves a large number of women and men and allows differences in important subgroups to be studied and detected. Finally, patients prescribed ACE inhibitors were much less likely to reach target doses. Although we adjusted for dose in our analysis, we cannot exclude that part of our results may be explained by a dose effect. Nevertheless, the "real world" difference is of considerable interest and underlines the importance of undertaking effectiveness, as opposed to efficacy, studies.

The results of our study could be explained on the basis of differences in blood pressure reduction achieved in women and men on ARBs compared to ACE inhibitors rather than mechanisms specific to the two classes of drugs studied. Indeed, treatment with any commonly used anti-hypertensive regimen has been shown to reduce the risk of death and larger reductions in blood pressure produce larger reductions in risk [20]. In our cohort, women and men on ARBs were more commonly treated with calcium channel blockers. Thus, women and men on ARBs may have had lower blood pressures than those on ACE inhibitors. Since we do not have the actual blood pressure data of the patients studied we cannot verify this hypothesis. However, we attempted to minimize the effect of blood pressure reduction on our results by adjusting for differences in the rates of a number of other drugs prescribed at discharge and by performing stratified analysis.

The results of the study could also be explained by the fact that more women and men on ARBs were hypertensive than those on ACE inhibitors and more women and men on ACE inhibitors had a history of myocardial infarction than those on ARBs. Hypertension is more commonly related to diastolic dysfunction and myocardial infarction to systolic dysfunction. Furthermore, survival in patients with CHF and diastolic dysfunction is better than in patients with CHF and systolic dysfunction [21]. Unfortunately, we do not have the individual patient characteristics to verify the aetiology of the patients' heart failure and their left ventricular function. However, we tried to minimize the possible confounding effect of the nature of heart failure by adjusting for the differences in hypertension and myocardial infarction prevalence in the analysis.

Genetic polymorphisms have been shown to be important in the pathophysiology and the response to treatment of CHF [22-24] and could also explain our results. For example, a new gene in the ACE family, the ACE2 gene, has been identified and shown to map to defined quantitative trait loci on the X chromosome [3,4]. Although there is significant homology in their respective protein sequences, ACE and ACE2 appear to have opposing roles. Whereas ACE activity leads to the formation of angiotensin II, the disruption of ACE2 in mice leads to an increase in the level of angiotensin II, impaired cardiac contractility and upregulation of hypoxia-induced genes in the heart. In addition, mice deficient in both ACE and ACE2 show completely normal heart function [25]. Thus ACE and ACE2 are thought to negatively regulate each other [26-29]. However, at this point, the full role of ACE2 in vivo and its impact on differences in response to ACE inhibitors and ARBs in women compared to men with CHF remain unknown. The results of our study provide impetus to pursue this and other sex-related differences to identify optimal treatment of CHF in both men and women.

This study has limitations. First, the administrative databases used do not contain detailed clinical information. As with all observational studies [30], hidden biases or inability to account for all factors related to both physicians' prescription choices and patients' risk for death might be responsible for the observed differences between ACE inhibitors and ARBs. To reduce the possibility of residual confounding, we adjusted for multiple potentially confounding variables, including patient, physician and hospital characteristics. Second, as in most database pharmaco-epidemiologic studies [31], exposure time to drug was measured by filled prescriptions, which may not faithfully measure pill intake. Dosage measurement was imprecise and was categorized grossly according to "target dosage". However, the severity of the disease under study increases the chances that patients will have taken the medications as prescribed. In addition, it is unlikely that the interruption in timing and its effect on mortality would vary from one class of drug to the other.

In conclusion, at the population level, sex appears to modify the effectiveness of treatment in CHF, with women having better survival with ARBs compared to ACE inhibitors whether they are hypertensive or not. These findings underscore the importance of assessing effectiveness of interventions at the population level, as opposed to the efficacy in randomized trials, and of undertaking studies into sex differences in treatment-related outcomes in heart disease. Since this is a retrospective, observational study of administrative databases, a prospective trial is needed to confirm these results before preferentially prescribing ARBs to women with CHF. Until additional evidence is available, therapy should be tailored to the individual patient, including sex, aetiology of heart failure and left ventricular function.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
{star} This study was undertaken as part of the Gender and Sex Determinants of Cardiovascular Disease (GENESIS) project, funded by the Canadian Institutes of Health Research, grant # 72565, and the Heart and Stroke Foundation of Canada.

1 Drs Hudson and Pilote are funded by the Canadian Institutes of Health Research. Dr Pilote is a William Dawson Professor of Medicine at McGill University. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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