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Effectiveness by gender and age of renin‐angiotensin system blockade in heart failure—A national register‐based cohort study

Abstract Purpose Investigate effectiveness by gender and age and equity implications of treatment with renin‐angiotensin system blockade (RASb) in heart failure (HF) patients. Methods In this population‐based register study, we used inpatient data from 2006 to 2010 for patients age 20 years or older with no HF hospitalisation for minimum of 1 year before an index hospitalisation. A wash‐out period for RASb of 6 months preceding admission was used. Hospital data were linked with drug dispensation data and cause of death data. The associations between time‐dependent RASb exposure and all‐cause death and HF death, respectively, were examined by Cox regression models. Interactions by gender and age were also investigated on the multiplicative and additive scales. Results Thirty thousand seven hundred twenty‐one patients were analysed. Fifty‐one percent were women. Median age was 83. Fifty‐three percent of women and 64% of men received RASb after the index hospitalisation. Younger patients were more likely to receive RASb than older ones. One‐year mortality was 28%. RASb was associated with an overall hazard ratio (HR) for all‐cause death of 0.72 (95% confidence interval 0.69‐0.75), and an HR of 0.85 (0.77‐0.93) for HF death. Interaction analyses showed HRs for all‐cause death associated with RASb between 0.12 (0.10‐0.13) in the youngest, and 0.80 (0.76‐0.84) in the oldest patients. Conclusions RASb appeared effective for women and men and for patients of all ages in this hospitalised HF cohort. No gender difference in effectiveness was found. RASb exposure was low overall, indicating a need for improved adherence to treatment guidelines. Treatment with RASb may be inequitable for women and older patients.


| INTRODUCTION
Efficacy of renin-angiotensin system (RAS) blocking drugs in heart failure (HF) with reduced ejection fraction (HFrEF) is established in clinical trials, [1][2][3] where mortality reductions are seen across gender, age, and ethnicity groups. 1,[4][5][6] Hence, treatment guidelines recommend RAS blockade (RASb) for the vast majority of HF patients. 7 Effectiveness 8 studies (ie, observational studies of RASb use in HF patients) also show mortality reductions overall and that RASb is effective among elderly and female patients, [9][10][11][12][13] although women may benefit less than men. 11,14 Although RASb reduces mortality by 16% to 40% in patients with HFrEF, [1][2][3] under-prescription as well as gender and age inequity in RASb treatment have been demonstrated. 9,[15][16][17] Equitable health care requires efficacy studies in different patient groups, as effects and side effects may vary. 18,19 Women and older patients are typically underrepresented in HF research. 20 To our knowledge, no previous study has analysed total population data for RASb effectiveness according to age and gender in HF.

| Aim
Building on our previously reported data, revealing less RASb treatment among female and elderly HF patients, 15 we aimed to study the effectiveness of RASb in the same cohort.
The research questions were as follows: • Is RASb exposure associated with mortality reduction in a hospitalised Swedish HF population?
• Does the association between RASb exposure and mortality differ by gender or age? 2 | METHODS

| Material
This population-based cohort study used register data from the Swedish National Patient Register, [22][23][24] the Swedish Prescribed Drug Register, 25,26 and the Swedish Cause of Death Register. 27 The registers are held by the Swedish National Board of Health and Welfare.
The coverage of the patient register is over 99% for inpatients. The Prescribed Drug Register records dispensed drugs in Sweden with 95% to 100% completeness. 25 The Cause of Death register comprises all deaths among persons registered in Sweden at the time of death, with a coverage of 99%. 27

KEY POINTS
• Despite evidence of efficacy of renin-angiotensin system blockade (RASb) in heart failure (HF), RASb is underused, particularly in female and older patients.
• RASb effectiveness in unselected HF patients is incompletely understood-some data suggest less effectiveness among women.
• This study investigated effectiveness of RASb by gender and age among HF patients.
• RASb appeared effective in women and men. No gender difference in effectiveness was found. RASb seemed effective in all age groups, although less among older patients.
• HF treatment may be inequitable for women and older patients, but more detailed clinical data are needed to determine RASb eligibility. a time-dependent exposure variable for RASb was computed, such that follow-up time before the first dispensation was defined as unexposed time, and follow-up time after the first dispensation (until death, censoring, or end of study) was defined as exposed time, to avoid survival bias. Only the first dispensation was considered, ie, exposure information was not updated. No specific assumptions regarding the length of prescription were made. Stock-piling and nonadherence were not addressed. RASb exposure was defined as protective.

| Gender
Gender was categorised as woman or man. Female gender was considered protective; thus man was the reference.

| Age
Age was categorised as 20 to 64 years, 65 to 74 years, 75 to 84 years, and 85 years or older. The highest age category was as the reference.
As entry time into the study varied for the subjects, hospitalisationfree time in the study period before the index hospitalisation was computed.
Other HF therapies, ie, beta blocker (BB) and mineralocorticoid receptor antagonist (MRA) dispensed within 1 year following index, were recorded. where RERI>0 designates positive interaction, and RERI<0 designates negative interaction. 28 All exposures were coded as protective to facilitate interpretation of interaction effects.

| Statistical analysis
To examine whether misclassification of comorbidities would bias estimates, we first assumed that the misclassification was due to underreporting, ie, all patients recorded as having a diagnosis have it, but some patients coded as not having a diagnosis actually also have it. Although a simplification, it is reasonable to assume this to be true and that misclassification is one directional. Thus, the association between the measured confounder and the true confounder is always positive.
A directed acyclic graph ( Figure S1) was used to draw our assumptions about this one-directional association and about associations of comorbidity with RASb and death, respectively. Due to these assumptions and because misclassification should not depend on RASb exposure, we could follow a similar reasoning as Vanderweele 29 for unmeasured confounders. For comorbidity positively associated with both exposure and outcome, the magnitude of the exposureoutcome association was underestimated and for comorbidity negatively associated with the exposure and positively associated with the outcome, the association was overestimated. The bias thus depends on comorbidity diagnosis.
The significance level was 0.05, and tests were two-sided.

| Patient characteristics
Fifty-one percent were women (

| Treatment
RASb was dispensed to 58% of patients, and more commonly among men and younger, compared with women and older patients. All    comorbidities except hypertension and CABG were more frequent in the group not receiving RASb, with the largest difference in renal dysfunction (5% vs 13%) between RASb-exposed and nonexposed patients. Among those receiving RASb, BB was more prevalent compared with the non-RASb group (Table 1).

| Interaction analyses
The interaction term for female gender and RASb was nonsignificant for all-cause death. There was significant interaction between lower age class and RASb for all-cause death. (Table 2; model 6). Interaction effects are also depicted as HRs for allcause death for each exposure combination compared with a common reference category in Figure  The RERI for all-cause death was not significant for gender and RASb nor age and RASb (Table 2). For HF death, the interaction term for female gender and RASb was nonsignificant (Table 3). HRs for each exposure category are presented in Figure 3. The RERI was not significant (Table 3).

| DISCUSSION
Women and older patients were less exposed to RASb than men and younger patients. Exposure to RASb was associated with a reduction in mortality for women and men alike. Interaction analysis showed a stron-

| Mortality
The overall all-cause mortality of 28% at 1 year and 37% at 2 years in our study is similar to other observational studies. 10,11,13,32,33

| Treatment effects
Our overall adjusted HR of 0.72 for all-cause death among patients exposed to RASb is comparable with a systematic overview of randomised trials reporting an OR for death of 0.74 for ACEI compared with placebo. 4 11 In contrast, we found a somewhat higher risk reduction among women, although not statistically significant.
As in previous studies, we found less RASb exposure among women [15][16][17][18] and older patients. 10,36 Whether this constitutes inequity in treatment is unclear, as the gender difference in treatment could be due to a higher prevalence of HFpEF among women. 37

| Age
RASb exposure decreased with higher age. RASb was associated with better survival in all age groups, but the association weakened with higher age, perhaps partially due to a higher prevalence of HFpEF among older patients. 37  RASb reduces hospitalisations 4 and is cost-effective. 39

| Strengths and limitations
Our individual level data represent the entire Swedish population. The validity for HF as primary diagnosis in the patient register is 95%. 24 In the prescribed drug register, RASb registration is around 99% complete. The validity of HF as underlying cause of death has not been studied however, and there is uncertainty concerning the validity of the outcome HF death. Our comorbidity data are limited to inpatient hospitalisation data within 1.5 years preceding the index hospitalisation, and comorbidities were likely underestimated. Notably for HF, the lack of primary care data would lead to underreporting and misclassification bias. 40 The prevalence of several comorbidity diagnoses are lower than in some other studies 9,11,13,41 although Shafazand et al reported comorbidity levels similar to ours, also from Swedish patient register data. 33 Some comorbidities are found in similar proportions for certain groups by Keyhan et al. 11 As for misclassficiation, we believe that our cohort was actually among those unexposed. Our cohort resembles a de novo HF population and an RASb-naïve one and could be less affected by comorbidity including renal dysfunction than others. Furthermore, the relation between renal dysfunction and mortality in HF is graded; the more advanced renal dysfunction, the higher the mortality. 43 Clinically significant, ie, more advanced, renal dysfunction should be less likely to be underreported in the patient register. Patients with comorbid heart disease were more likely to be diagnosed with chronic kidney disease in the study by Gasparini et al. The overall HR for patients with renal dysfunction in our study was 0.78 (data not shown), which is close to the overall HR for the whole cohort of 0.72. While we cannot refute misclassification bias in comorbidity, the consistency with other studies in overall mortality and RASbassociated mortality reduction also supports the overall validity of our results.
A limitation shared with other register studies is the lack of characterisation of HFrEF/HFpEF, as the patient register does not contain data on ejection fraction (EF). RASb has not been shown to increase survival in HFpEF patients and is not recommended for HFpEF in guidelines. We were unable to validate true eligibility for RASb.
Survival bias in pharmacoepidemiology typically leads to overestimation of effects. 45 A strength of our study is that we addressed this by using a time-dependent exposure covariate.
Interaction was estimated on both the multiplicative and the additive scales and risks calculated for each exposure category with a common reference, as recommended in epidemiological literature. 28 While one study suggested that the RERI is valid only for risk factors and not preventive exposures, 46 a later publication concluded that it may be used for preventive factors when the sample size is sufficient (more than 1000 subjects). 47 We thus regard our RERI estimates as valid.
Obviously, this observational study cannot assert causation.

| CONCLUSIONS
We suggest that RASb is effective in hospitalised female and male HF patients of different ages, including very old patients. We found no evidence for a differential effect by gender. Exposure to RASb was associated with decreased mortality in all studied patient groups, although somewhat less in older patients. Yet, RASb exposure was low, and more pronounced so among older and female patients. There is a room for improvement in adherence to treatment guidelines. Further studies including data on EF would expand knowledge regarding equity in RASb treatment.

ETHICS STATEMENT
The study conforms to the declaration of Helsinki and was approved by the Swedish Central Ethical Review Board (reg. no. Ö 29-2011).