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European Journal of Heart Failure 2007 9(6-7):594-601; doi:10.1016/j.ejheart.2007.03.004
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© 2007 European Society of Cardiology

Angiotensin-converting enzyme inhibitors and survival in women and men with heart failure

Golyar Keyhan, Shun-Fu Chen and Louise Pilote*

Division of Clinical Epidemiology, The Research Institute of the McGill University Health Centre, 1650 Cedar Avenue, Room L10-421, Montreal, QC, Canada H3G 1A4

* Corresponding author. Tel: +1 514 934 1934x44722; fax: +1 514 934 8293. E-mail address: louise.pilote{at}mcgill.ca


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgment
 References
 
Background: Several randomized controlled trials demonstrate that angiotensin-converting enzyme (ACE) inhibitors improve survival in patients with congestive heart failure (CHF). However, whether ACE inhibitors benefit both sexes is not adequately addressed.

Purpose: Our objective was to determine the effectiveness of ACE inhibitors in women with CHF.

Methods: The Quebec hospital discharge database was linked with the physician and drug claims database to identify a cohort with a discharge diagnosis of CHF between January 1998 and March 2003. In this retrospective cohort study, subjects who filled a prescription for ACE inhibitors (19,220 exposed) were compared to those who never filled such prescription (8617 non-exposed). The primary outcome was survival by exposure to ACE inhibitors.

Main findings: There were 14,693 women (67% exposed) and 13,144 men (72% exposed). The 1 year mortality was 19.5% and 30% in those exposed and non-exposed, respectively. A significant survival benefit was demonstrated in both sexes exposed to ACE inhibitors [adjusted hazard ratio (95% confidence interval): women 0.80 (0.76–0.85); men 0.71 (0.67–0.75)].

Principal conclusions: ACE inhibitors improve survival in both sexes with CHF, but the protective effect appears to be greater in men. Our results support the current recommendations for the management of women with CHF.

Key Words: Angiotensin-converting enzyme inhibitors • Congestive heart failure • Sex • Survival • Medication exposure

Received May 3, 2006; Revised December 4, 2006; Accepted March 8, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgment
 References
 
Heart failure is a major health problem with significant morbidity and mortality. Hospitalizations for congestive heart failure (CHF) continue to increase with substantial contribution to this increase by women [1]. Randomized clinical trials on angiotensin-converting enzyme (ACE) inhibitors have established these medications as a mainstay in the treatment of CHF [2].

However, few studies have looked at the effects of ACE inhibitors specifically in women with CHF. The average proportion of women enrolled in ACE inhibitor trials of CHF has only been about 20% [3,4]. This under-representation is exacerbated by the exclusion of older patients from trials, as CHF predominates in older women. Some studies have included subgroup analysis but were not designed to specifically evaluate the effect of ACE inhibitors on women and men separately, and other studies have not compared differences in mortality between sexes at all. Moreover, there are no definitive randomized trials in patients with CHF on the basis of diastolic dysfunction, a group of patients predominantly composed of women [3]. Yet, ACE inhibitors are widely used and current guidelines recommend the same treatment for both sexes [2].

A randomized clinical trial specifically looking at the effects of ACE inhibitors in women with CHF is unlikely to be undertaken, and subgroup analyses of women have been underpowered [1,2,5]. However, whether ACE inhibitors have similar effects on mortality in women as in men with CHF remains unknown. We examined a large, population-based administrative database of all patients (women and men) admitted for CHF in the province of Quebec, Canada, between the years 1998 and 2003. Our objective was to determine the effectiveness of ACE inhibitors on mortality in women and men with CHF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgment
 References
 
2.1. Study population
The Quebec hospital discharge summary database, which includes information on all CHF hospitalizations, and the provincial physician and drug claims database were used in this study. Patients were identified if they were admitted to hospital with a diagnosis of CHF (International Classification of Disease Ninth revision, code 428) between January 1, 1998 and March 31, 2003 (index admission). Follow-up information was available until March 31, 2004. The physician and drug claims database for the province of Quebec provides survival status for more than 99% of the patients. The reliability of coding for the diagnosis of CHF in administrative databases has been shown to be high [6,7] and the physician and drug claims database has been validated for the accuracy of prescription claims [8]. This cohort has been used by other epidemiological studies [9].

Only patients ≥65 years of age were included, as data on medication was available for this age group alone and we excluded patients older than 105 years. In case of multiple hospital transfers, we considered them as one hospitalization, and the total length of hospital stay was calculated; this was done in order to avoid multiple counting of the same health event. We excluded patients with CHF coded as an in-hospital complication, or with previous CHF admissions within the preceding 3 years. This 3-year wash-out period was used to ensure that groups were of comparable severity of illness, and also to minimize the proportion of patients for whom the prescription of ACE inhibitors was not new. This was done in order to obtain a more homogenous population including only subjects with a first CHF admission rather than a mixture of patients with a different number of admissions. Patients discharged to a long-term care institution, rehabilitation centre, other province, or psychiatric unit were also excluded due to lack of information on prescriptions.

2.2. Clinical Characteristics
A clinical model specific to CHF has been established by Lee and colleagues [10] to predict mortality in patients with CHF using administrative databases. We used this clinical CHF model which includes: age, cerebrovascular disease, myocardial infarction, malignancy, liver disease, diabetes, dementia, chronic renal failure, atrial fibrillation, rheumatologic disorders, chronic obstructive lung disease, hypertension, peripheral vascular disease and cardiac procedures at baseline. Cardiac medications that could influence survival rates in CHF were identified at the time of hospital discharge. Information on the admitting physician (cardiologist, internist, or general practitioner), type of admitting hospital (teaching or not teaching university affiliation), year of hospitalization for CHF (to account for temporal trends) and the hospital's annual volume of CHF admissions (low ≤31, medium ≤121 and >31, and high >121 admissions for CHF/year) was obtained.

2.3. ACE inhibitor exposure
ACE inhibitor exposure was defined as a filled prescription at any time during the study and no exposure to ACE inhibitor was defined as no filled prescription ever. This classification of exposed subjects requires that a person survives until the date of their filled prescription. This introduces an artificial survival advantage associated with the exposed group regardless of the effectiveness of the treatment. To minimize this survival bias in our study, the method of "prescription time distribution matching" was used [11]. The time that an exposed person filled her/his prescription was considered as time zero. The number of days from hospital discharge to time zero (the time that the first ACE inhibitor prescription was filled) was assessed for exposed. For non-exposed, a time zero was matched and assigned to them, in a manner that the overall distribution of time zero of the non-exposed, was matched to that of the exposed time of first prescription. Both groups are followed from time zero to death, or the end of the study follow-up, whichever came first. Non-exposed persons who had an event prior to the assigned time zero were excluded from the analysis (482 subjects).

The patterns of drug use were characterized by several measures. Among patients with ACE inhibitor exposure, we calculated the proportion of time for which a patient was covered by prescriptions during the study or until death. This measure was calculated using a variable indicating the duration of each filled prescription available in the drug claims database. We also calculated the mean time to first prescription, the percent target dose achieved, and any switch from one ACE inhibitor to another.

2.4. Outcomes
The primary outcome was the survival in women and men exposed to ACE inhibitors compared to those unexposed.

2.5. Statistical analysis
All variables were described according to sex and ACE inhibitor exposure status. Clinical characteristics of women and men were compared by the chi-square test. Continuous variables were compared by the Student's t test.

A multivariate analysis was performed using Cox proportional hazards model to predict the determinants of mortality. In all models, adjustments were made for age, sex, baseline comorbidities, admitting service, cardiac procedures, other discharge medications, year of hospitalization for CHF and the hospital's annual volume of CHF admissions. In an intention-to-treat analysis, patients with filled prescriptions for ACE inhibitors were assumed to be taking it throughout the follow-up with censoring at death or end of follow-up. Results are expressed as hazard ratios (HRs) with 95% confidence intervals (CIs).

We also determined whether there was a relation between ACE inhibitor exposure and sex by calculating the interaction term between these variables.

Adjusted survival curves were constructed from proportional hazards models as described by Ghali and colleagues [12]. In this method, survival curves are first calculated for each combination of covariates in a database. A weighted average of these individual curves was then calculated, with weights proportional to the number of individuals at each level of covariates.

2.6. Sensitivity analyses
In order to identify any selection bias due to our classification of the groups, we repeated the same analyses while categorizing the exposed and non-exposed groups differently. In one analysis, the exposed group included only those subjects who filled a prescription for an ACE inhibitor during the first 90 days after discharge, and the non-exposed group included only those who never filled a prescription for ACE inhibitors. Another classification defined the exposed group similarly, but the non-exposed subjects included both those who never filled a prescription and those who filled a prescription for ACE inhibitors after the first 90 days.

It is possible that those who were not prescribed any ACE inhibitors were sicker and, therefore, would have a worse survival independent of their medication exposure. To assess for the possibility of this selection bias based on disease severity, discharge medications were used to stratify the groups into different levels of disease severity. We constructed a variable for disease severity based on cardiac medications recommended by the AHA/ACC guidelines [2] for the management of CHF. These guidelines recommend cardiovascular medications useful for the treatment of various stages of heart failure (stages A to D, in increasing degree of severity). We considered cardiac medications recommended in stages C and D of CHF as markers of disease severity. Thus, subjects who were discharged on digoxin, amiodarone, hydralazine, spironolactone, metalozone, or diuretics were classified as a higher level of disease severity than those on none of these medications.

2.7. Ethics approval
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. The study was approved by the McGill University Ethics Review Board.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgment
 References
 
3.1. Patient characteristics
The cohort included 27,837 patients with 14,693 (53%) women and 13,144 (47%) men (Tables 1A and 1B). Women were older and had more hypertension (44% versus 30%, respectively); whereas men had more myocardial infarction (25% versus 19%, respectively).


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  		Table 1A Baseline characteristics of 27,837 women and men with congestive heart failure by ACE inhibitor exposure

 


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  		Table 1B Treatment at the time of hospital discharge of 27,837 women and men with congestive heart failure by ACE inhibitor exposure

 
In both sexes, a greater number of ACE inhibitors users had diabetes, hypertension, and myocardial infarction, whereas more non-exposed patients had chronic obstructive pulmonary disease and chronic renal failure (Table 1A). Those who had a coronary angiography performed in the hospital were more likely to be exposed to ACE inhibitors than those without the procedure (Table 1B).

3.2. Medical therapy
There were 19,220 (69%) patients who filled a prescription for an ACE inhibitor and 8617 (31%) patients who never filled a prescription for an ACE inhibitor (Table 1A). Sixty-seven percent of women (9801) and 72% of men (9419) were exposed to ACE inhibitors.

Patients exposed to ACE inhibitors (in both groups of women and men) had more prescriptions at the time of hospital discharge for β-blockers, digoxin, nitrates, spironolactone, loop diuretics, statins and warfarin; whereas in those not exposed to ACE inhibitors, there were more prescriptions for hydralazine and angiotensin receptor blockers (ARBs) (Table 1B). No difference between women and men was seen based on the admitting physician (data not shown).

3.3. Prescription characteristics
The patterns of drug use were similar for both women and men (Table 2). Adherence to ACE inhibitors was high in both groups once prescribed. The mean duration of follow-up was about two and half years in both sexes. Analysis based on ACE inhibitor dosage did not show any significant difference in usage between women and men, and there was no dose-response relationship.


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  		Table 2 Patterns of ACE inhibitor prescription in women and men with congestive heart failure

 
3.4. Effectiveness of ACE inhibitors on mortality
A significant improvement in survival was achieved with exposure to ACE inhibitors in both sexes. The unadjusted HRs were 0.75, 95% CI 0.71-0.78 in women and 0.62, 95% CI 0.59-0.65 in men. The 1 year mortality was 19.5% in those exposed and 30% in those non-exposed to ACE inhibitors.

After adjusting for potentially confounding variables based on the multivariate Cox proportional hazards model, adjusted HR was 0.80, 95% CI 0.76-0.85 in women, and 0.71, 95% CI 0.67-0.75 in men (Table 3). The other protective factors were the presence of systemic hypertension and having a cardiologist as the admitting physician. β-Blocker and statin prescriptions at hospital discharge improved survival in both sexes. ARBs improved survival in women only (adjusted HR 0.81, 95% CI 0.72-0.91 in women, and adjusted HR 0.92, 95% CI 0.81-1.05 in men). There was a survival benefit in both women and men who had a coronary angiography during the hospital admission, but coronary artery bypass graft surgery significantly improved survival in men only (adjusted HR 0.76, 95% CI 0.53-1.11 in women and adjusted HR 0.50, 95% CI 0.36-0.70 in men). The presence of diabetes, cerebrovascular disease, malignancy, chronic obstructive pulmonary disease, chronic renal failure and peripheral vascular disease predicted a significantly worse survival in both women and men.


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  		Table 3 Factors associated with survival in women and men based on multivariate analysis

 
When looking at all subjects together, men had a worse survival than women (adjusted HR 1.3, 95% CI 1.2-1.3 in men) (Fig. 1) and there was an interaction between sex and ACE inhibitor (adjusted interaction term 0.89, CI 0.83-0.95). Non-exposed men had a higher relative risk (RR) of death compared to non-exposed women (this group was used as a reference). Once exposed to ACE inhibitors, there was a significantly greater decrease in RR of death in men than in women (Fig. 2).


Figure 01
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  		Fig. 1 Risk-adjusted survival curves were plotted from proportional hazards model using the corrected group prognosis [12] comparing ACE inhibitor exposure and non-exposure in women and men.

 


Figure 02
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  		Fig. 2 Interaction term between ACE inhibitor and sex.

 
3.5. Sensitivity analyses
Different classifications of the exposed and non-exposed groups revealed comparable survival benefits in both sexes. When the exposed group included only those with a filled prescription within 90 days of discharge compared to those who never filled a prescription, the HR was 0.77, 95% CI 0.73-0.81 in women, and 0.68, 95% CI 0.64-0.71 in men. Classification of the exposed group as those who filled a prescription within 90 days of discharge, and the non-exposed group as both those who filled a prescription after 90 days and those who never filled a prescription for ACE inhibitor demonstrated a HR of 0.88, 95% CI 0.84-0.92 in women, and 0.80, 95% CI 0.76-0.84 in men.

Categorization of subjects into different disease severity groups revealed that the survival advantage with ACE inhibitors persisted and was independent of disease severity (0.81, 95% CI 0.76-0.85 and 0.81, 95% CI 0.74-0.89 in women; 0.71, 95% CI 0.67-0.75 and 0.65, 95% CI 0.59-0.71 in men, for those not prescribed and prescribed other cardiac medications, respectively).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgment
 References
 
The results of our study demonstrate that ACE inhibitors are associated with improved CHF survival in both sexes with a decrease in mortality of 20% in women and 29% in men. The survival advantage associated with ACE inhibitor exposure persisted and was independent of disease severity for both sexes. The number of women (14,693) in this large unselected population of CHF patients is much higher than prior CHF trials with similar characteristics [2-5].

The benefit of ACE inhibitor usage in women is controversial in the literature. Pooling 30 studies of ACE inhibitors and heart failure [13] with a total of 1587 women, showed a significant 37% decrease in mortality and/or hospitalization in men as compared with only a 22% reduction in women with a CI that included the null (CI 0.59-1.09). In the meta-analysis by Shekelle et al. [14], the combined number of women included in all 6 major CHF trials with ACE inhibitors was 2373, and ACE inhibitor usage achieved statistical significance in women with HR 0.84 (95% CI 0.72-0.98). When women were divided into treatment (symptomatic) or prevention (asymptomatic) groups, there was no significant benefit of ACE inhibitors (RR 0.90, 95% CI 0.78-1.05 and RR 0.96, 95% CI 0.75-1.22, respectively). The survival advantage determined in this meta-analysis was similar to that found in our study (HR 0.80, 95% CI 0.76-0.85).

In a pre-planned subgroup analysis of women enrolled in the HOPE trial [15], including a total of 2480 high-risk women without clinical CHF or known left ventricular systolic dysfunction, treatment with ramipril resulted in a trend towards reduced hospitalization for heart failure (RR 0.88, 95% CI 0.58-1.34) and all heart failure (RR 0.81, 95% CI 0.65-1.07), although neither outcome was statistically significant. The apparent lack of significant benefit of ACE inhibitors for women in these analyses may be explained by the small number of women involved.

There are few studies looking at heart failure in the elderly, where CHF is not only common but also commonly fatal, with fewer than 30% of elderly persons surviving 6 years after their first hospitalization for heart failure [16]. Our study supports the poor prognosis in this age group (mean age±standard deviation: for the whole group, 78.4±7.5; for women, 79.9±7.5; for men, 76.7±7.0) with a 1 year mortality of 19.5% in those exposed, and 30% in those non-exposed to ACE inhibitors. A study is underway to evaluate the medical management of very old patients with CHF compared with younger patients [17].

Overall, men with CHF had a worse survival than women in our study, a finding that is consistent with other studies in the literature [18-22]. The cohorts differed in term of age and the presence of hypertension which were both higher in women, and myocardial infarction which was more common in men. However, adjustments were made for all the baseline characteristics and would not explain the survival benefit seen in women. A growing body of basic and clinical data point to fundamental sex-related differences in the nature and extent of myocardial hypertrophy and adaptation, which might account for the survival advantage for women. Krumholz et al. [23] showed sex differences in patients with systolic hypertension; men demonstrated maladaptive remodelling with left ventricular dilation and eccentric left ventricular hypertrophy in comparison with more "adaptive" remodelling with concentric hypertrophy and small cavity size in women. Similarly, more marked left ventricular hypertrophy, with small cavities, lower end-systolic wall stress and better preservation of left ventricular ejection performance, has been reported in women compared with men with aortic stenosis [24]. Therefore, it is possible that maladaptive remodelling may be more frequent in men, contributing to their higher mortality.

Although non-exposed men had a higher RR of death compared to non-exposed women, once subjects were exposed to ACE inhibitors, there was a significantly greater decrease in RR of death in men than in women (Fig. 2). The presence of a significant interaction term (HR 0.89, CI 0.83-0.95) in our study suggests that ACE inhibitors may act differently in women and men with CHF. Recently, 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 [25,26]. ACE and ACE2 appear to have opposing roles. 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; whereas activation of ACE leads to increases in angiotensin II [27,28]. In addition, mice deficient in both ACE and ACE2 show completely normal heart function [29]. Thus, these 2 genes seem to negatively regulate each other [30,31]. However, the in vivo role of ACE2 and its impact on differences in response to ACE inhibitors in women compared with men with CHF remain unknown. Similarly, sex differences in myocardial adaptation to pressure overload, lower rates of aging-related cardiac myocyte cell loss and reactive hypertrophy, and up-regulation of left ventricular ACE activity during pressure overload hypertrophy have been described [21,22,32]. These sex differences may account for the disparity in the outcome of ACE inhibitor exposure between women and men.

ARBs have been shown to improve survival in patients with CHF compared with placebo [33], and demonstrate comparable survival benefit to ACE inhibitors [34]. There is also evidence that ARBs in addition to ACE inhibitors reduce cardiovascular mortality in patients with CHF [35] and decrease hospital admissions for CHF [36]. Our study showed a survival benefit in women exposed to ARBs (HR 0.81, 95% CI 0.72-0.91), but not in men (HR 0.92, 95% CI 0.81-1.05). Although there was a small proportion of ARB usage in our study, the result is consistent with the report of Hudson et al. [37] where in nearly 20,000 elderly women and men with CHF, ARBs were associated with improved survival compared with ACE inhibitors in all women, whether hypertensive or not. In contrast, in non-hypertensive men ACE inhibitors were associated with better survival, while the survival in hypertensive men was comparable between ACE inhibitors and ARBs users. The latter was confirmed also in our study, where there were less hypertensive men, and ACE inhibitors had a greater survival benefit in men than women who were more hypertensive. For these reasons, ACE inhibitors and ARBs were not combined in the analyses. If we collapsed the two drug categories, the different effect of ARBs between women and men would not be revealed and would be diluted by the predominant ACE inhibitor exposed group. Since this is a retrospective, observational study of administrative databases, a prospective trial is required to confirm these results.

The limitations of our study include the lack of detailed clinical information in the database and the inability to account for physicians' prescription choices. However, we attempted to identify any bias due to comorbidities and disease severity by reclassifying subjects into different levels of disease severity based on the presence or absence of prescriptions of other cardiac drugs. This analysis demonstrated a similar magnitude of benefit with ACE inhibitor exposure in both sexes, independent of their disease severity. We have no information on the intensity of follow-up between groups, but there is no reason why one group would be followed more intensely than another except for their disease severity which was taken into consideration. Due to the nature of the database, we were unable to analyze the data in relation to functional class or left ventricular ejection fraction. It is known that women in this age group have more preserved ejection fraction than men, and ACE inhibitors have been shown to provide survival benefit in subjects with low ejection fraction. It is likely that these facts may have influenced the prescription of ACE inhibitors by the treating physician, which could explain the higher percentage of unexposed women compared to unexposed men. A recent study showed that patients with CHF with preserved ejection fraction were more likely to be older and female and to have a history of hypertension and atrial fibrillation; however, the survival of these patients with preserved ejection fraction was similar to that of patients with reduced ejection fraction [38]. Nevertheless, a study specifically designed to evaluate the effects of ACE inhibitor exposure in relation to ejection fraction in women is necessary to resolve these issues.

Our results apply only to patients over 65 years of age who were hospitalized with CHF. They do not apply to the outpatient CHF population. However, the mean age of our patients was 78.4 (standard deviation: 7.5) years. Thus, we believe that our study population is representative of the hospitalized CHF population seen in clinical practice. Patients with a filled prescription for an ACE inhibitor were assumed to be taking the drug throughout the follow-up period, based on the intention-to-treat analysis. This approach is unlikely to have altered our results, as there was high adherence to ACE inhibitors once prescribed. Finally, as in most pharmaco-epidemiological studies [39], filled prescriptions were used as a measure of exposure time to ACE inhibitors. This method may not faithfully measure actual pill intake. However, the mean time during which a patient had an ongoing prescription was high in both groups.

This is the first analysis of an administrative population-based database that examines the effects of ACE inhibitors in a large group of women with CHF. We found that ACE inhibitors are associated with improved survival in these women and this finding supports the current recommendations for the treatment of women with CHF. The greater decrease in RR of death in men exposed to ACE inhibitors highlights the importance of studying sex-related differences in the optimal treatment of CHF.


   Acknowledgment
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgment
References
 
This study was undertaken as part of the Gender and Sex Determinants of Cardiovascular Disease (GENESIS) project, and was funded in part by a grant from the Canadian Institute for Health Research (grant # 72565) and the Heart and Stroke Foundation of Canada. Dr. Keyhan is a Fellow in the Department of Endocrinology and Metabolism at McGill University. Dr. Pilote is a research scholar of the Canadian Institutes of Health Research (CIHR) and a William Dawson Professor at McGill University.

Authors' Agreement.

Each author participated in the conception, study design and analysis of data. They have taken part in drafting and revising the manuscript and have seen and approved the final submitted version to the European Journal of Heart Failure.


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

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