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Original Contribution |

Association Between Use of Renin-Angiotensin System Antagonists and Mortality in Patients With Heart Failure and Preserved Ejection Fraction FREE

Lars H. Lund, MD, PhD; Lina Benson, MSc; Ulf Dahlström, MD, PhD; Magnus Edner, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Medicine, Unit of Cardiology (Drs Lund and Edner) and Department of Clinical Science and Education (Ms Benson), Karolinska Institutet, Stockholm, Sweden; Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden (Dr Lund); Division of Cardiovascular Medicine, Department of Medicine and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden (Dr Dahlström); and Department of Cardiology, University Hospital Linköping, County Council of Östergötland, Linköping, Sweden (Dr Dahlström).


JAMA. 2012;308(20):2108-2117. doi:10.1001/jama.2012.14785.
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Published online

Context Heart failure with preserved ejection fraction (HFPEF) may be as common and as lethal as heart failure with reduced ejection fraction (HFREF). Three randomized trials of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ie, renin-angiotensin system [RAS] antagonists) did not reach primary end points but may have had selection bias or been underpowered.

Objective To test the hypothesis that use of RAS antagonists is associated with reduced all-cause mortality in an unselected population with HFPEF.

Design, Setting, and Patients Prospective study using the Swedish Heart Failure Registry of 41 791 unique patients registered from 64 hospitals and 84 outpatient clinics between 2000 and 2011. Of these, 16 216 patients with HFPEF (ejection fraction ≥40%; mean [SD] age, 75 [11] years; 46% women) were either treated (n = 12 543) or not treated (n = 3673) with RAS antagonists. Propensity scores for RAS antagonist use were derived from 43 variables. The association between use of RAS antagonists and all-cause mortality was assessed in a cohort matched 1:1 based on age and propensity score and in the overall cohort with adjustment for propensity score as a continuous covariate. To assess consistency, separate age and propensity score–matched analyses were performed according to RAS antagonist dose in patients with HFPEF and in 20 111 patients with HFREF (ejection fraction <40%) in the same registry.

Main Outcome Measure All-cause mortality.

Results In the matched HFPEF cohort, 1-year survival was 77% (95% CI, 75%-78%) for treated patients vs 72% (95% CI, 70%-73%) for untreated patients, with a hazard ratio (HR) of 0.91 (95% CI, 0.85-0.98; P = .008). In the overall HFPEF cohort, crude 1-year survival was 86% (95% CI, 86%-87%) for treated patients vs 69% (95% CI, 68%-71%) for untreated patients, with a propensity score–adjusted HR of 0.90 (95% CI, 0.85-0.96; P = .001). In the HFPEF dose analysis, the HR was 0.85 (95% CI, 0.78-0.83) for 50% or greater of target dose vs no treatment (P < .001) and 0.94 (95% CI, 0.87-1.02) for less than 50% of target dose vs no treatment (P = .14). In the age and propensity score–matched HFREF analysis, the HR was 0.80 (95% CI, 0.74-0.86; P < .001).

Conclusion Among patients with heart failure and preserved ejection fraction, the use of RAS antagonists was associated with lower all-cause mortality.

Figures in this Article

Up to half of patients with heart failure have normal or near-normal ejection fraction,1 termed heart failure with preserved ejection fraction (HFPEF) or diastolic heart failure. The mortality in HFPEF may be as high as in heart failure with reduced ejection fraction (HFREF) or systolic heart failure,1 but there is no proven therapy.

Whether HFPEF and HFREF are distinct or similar disorders remains controversial,2,3 but there is considerable overlap, with elevated filling pressures and classic heart failure signs and symptoms.4 For example, diastolic dysfunction and impaired systolic contractility occur in both HFREF and HFPEF.5 Renin-angiotensin-aldosterone system and other neurohormonal activation occurs in both HFREF and HFPEF.4,6 Renin-angiotensin-aldosterone system is also involved in precursors to and processes associated with HFPEF, such as hypertension, vascular dysfunction, and myocardial hypertrophy and fibrosis,68 which lead to increased stiffness, impaired relaxation, and diastolic dysfunction.6,7 Renin-angiotensin system (RAS) antagonists (angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers) inhibit the maladaptive remodeling associated with both HFREF and HFPEF and their precursors,6,8 and improve outcomes in HFREF.9,10

These observations provide a rationale for RAS antagonists in HFPEF. However, in 3 randomized controlled trials (RCTs),1113 RAS antagonists did not improve primary outcomes in HFPEF. However, there were signals toward benefits in primary outcomes or significant benefits in secondary outcomes. Selection bias, underpowering, or high crossover rates may have concealed a real benefit.14 Therefore, we hypothesized that RAS antagonists are associated with reduced mortality in a broad unselected population with HFPEF.

The Swedish Heart Failure Registry has been described.15,16 The inclusion criterion was clinician-judged heart failure. Eighty variables were recorded at discharge from hospital or outpatient visit and entered into a web-based database managed by the Uppsala Clinical Research Center in Sweden. The database is run against the Swedish death registry monthly. The protocol, registration form, and annual report are available at http://www.rikssvikt.se (in Swedish). Establishment of the registry and analysis of data were approved by a multisite ethics committee. Individual patient consent was not required, but patients were informed of entry into national registries and allowed to opt out. The registry and this study conform to the Declaration of Helsinki.

Propensity Scores

Propensity scores for treatment with RAS antagonists were estimated for each patient with logistic regression using 43 clinically relevant baseline variables. The propensity score is the propensity from 0 to 1 to receive a treatment given a set of known variables and is used to attempt to adjust for potential selection bias, confounding, and differences between treatment groups in observational studies.17,18 Continuous variables, including N-terminal pro-brain natriuretic peptide, were modeled using restricted cubic splines in the logistic regression. Missing data were handled by estimating separate logistic regressions for each missing variable pattern on all available observations. Each individual then received the propensity score that incorporated all nonmissing variables for that individual.

We constructed an age-matched and propensity score–matched cohort.19 The matching may be considered a form of adjustment for the propensity score (and the 43 variables used to derive the propensity score). Matching was 1:1 and without replacement, with each untreated patient matched to the closest treated patient in which age differed by 5 years or less and the propensity score differed by 0.1 or less. This yielded 3329 patients in each group.

All-Cause Mortality

Crude survival by RAS antagonist use (yes vs no) in the overall cohort was charted using the Kaplan-Meier method and compared in a univariable Cox regression. Thereafter, we performed several adjusted Cox regression analyses. The primary analysis was the matched cohort. Survival for the matched cohort was charted in the same figure as the crude survival in the overall cohort. Because propensity score matching excludes patients and impairs generalizability, we performed a secondary analysis in the overall cohort with adjustment for propensity score as a continuous covariate. Because higher age and lower creatinine clearance are associated with increased mortality and are also common reasons to avoid RAS antagonists, we also performed separate analyses with adjustment for these 2 variables alone in the overall cohort.

The scaled Schoenfeld residuals and difference of the freedom β from the models were investigated to detect violations to the proportional hazards assumption and possible influential outliers, respectively; none were found. Continuous variables, including the propensity score, were modeled using restricted cubic splines. Interactions between RAS antagonist use and ejection fraction and other selected baseline variables in the matched cohort were estimated by Cox regression and displayed in a forest plot.

Power Calculation

To test the null hypothesis that there is no difference in mortality between use and nonuse of RAS antagonists, 3170 patients or more would be needed in the smallest group. This assumed a hazard ratio (HR) for mortality associated with use of RAS antagonists of 0.90, 1-year mortality of 20%, an accrual period of 7 years (from our population), a power level of 80%, and 2-sided significance level of .05. The HR of 0.90 was conservatively estimated from the 95% confidence interval for the primary end points in the Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) study at 1 year (95% CI, 0.474-1.010),12 in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) preserved study throughout follow-up (95% CI, 0.77-1.03),11 and in the CHARM overall study10 throughout follow-up (95% CI, 0.83-1.00) without heterogeneity with respect to ejection fraction. The 20% 1-year mortality was based on 1-year mortality of greater than 20% in previous epidemiological studies of HFPEF20,21 and our overall registry.15

Consistency Analyses

Propensity scores were calculated from known and measured potential confounders (n = 43 in our study). However, unmeasured confounders may affect the results if they (1) are unrelated to or not fully accounted for by measured confounders, (2) affect the decision to prescribe a RAS antagonist, and (3) are associated with mortality independent of RAS antagonist use.2224 Therefore, we quantified the effects of hypothetical unmeasured confounders in the matched cohort16,25 (eTables 1-2. In patients with HFREF, use of a higher dose of a RAS antagonist is associated with greater benefit.26,27 Therefore, we performed an analysis in our patients with HFPEF who were matched by age and propensity score for a target dose of 50% or greater and a target dose of less than 50% vs no treatment (eTables 3 and eFigures 1–2).

In patients with HFREF, use of RAS antagonists has been shown to reduce mortality.9,10 Therefore, we performed a positive-control analysis of the association between use of RAS antagonists and mortality in patients with HFREF in the same registry (eFigure 1 and eFigure 3).

The level of significance was set at .05 and all reported P values and 95% confidence intervals are 2-sided. Statistical analyses were performed using R version 2.14.2 (R Foundation for Statistical Computing).

Patients

Between May 11, 2000, and October 10, 2011, there were 64 140 registrations from 64 of 77 hospitals and 84 of 1011 primary care outpatient clinics in Sweden. We included 16 216 first registrations with an ejection fraction of 40% or greater for the main analyses and the dose consistency analysis. We included 20 111 first registrations with ejection fraction of less than 40% for the HFREF consistency analysis.

Table 1 and Table 2 show baseline characteristics and standardized differences between use of RAS antagonists (yes vs no). Of 16 216 patients, 12 543 (77%) did receive RAS antagonists and 3673 (23%) did not receive RAS antagonists. Of the 12 543 patients, 73% received an ACE inhibitor, 25% received an angiotensin receptor blocker, and 2% received both. Specific agents and doses are listed in eTables 3.

Table Graphic Jump LocationTable 1. Characteristics of the Overall and Matched Cohorts and the Standardized Differences Between the Treatment Groupsa
Table Graphic Jump LocationTable 2. Medical History, Medications, and History of Interventions for the Overall and Matched Cohorts and the Standardized Differences Between the Treatment Groupsa

In the overall population, there were several differences between the groups, generally consistent with better health and more specialized care and planned follow-up in patients receiving RAS antagonists. The distribution of propensity scores was therefore different. In the matched cohort, the standardized differences between the groups were considerably smaller and few were statistically significant. The distribution of propensity scores was therefore similar, with lower propensity scores for treated patients and higher propensity scores for untreated patients compared with the overall cohort (Figure 1).

Place holder to copy figure label and caption
Figure 1. Distribution of Propensity Scores in the Matched and Overall Cohorts
Graphic Jump Location

Boxes represent median and interquartile range; whiskers represent minimum and maximum (if not outliers). Outliers are displayed with circles and are defined as observations more than 1.5 times the interquartile range from the first or third quartile, respectively. RAS indicates renin-angiotensin system.

The patients who were excluded due to missing ejection fraction or RAS antagonist treatment (eFigure 1) had a mean (SD) age of 82 (10) years, 53% were women, and had overall worse health and less treatment with neurohormonal antagonists (eTables 4–5).

All-Cause Mortality

In the overall HFPEF cohort, crude 1-year survival was 86% (95% CI, 86%-87%) for patients receiving RAS antagonists vs 69% (95% CI, 68%-71%) for patients not receiving RAS antagonists; and 5-year survival was 55% (95% CI, 54%-56%) vs 32% (95% CI, 30%-34%), respectively (unadjusted HR, 0.48 [95% CI, 0.45-0.51]; P < .001) (Figure 2 and Table 3).

Place holder to copy figure label and caption
Figure 2. Kaplan-Meier Survival Curves in the Matched and Overall Cohorts
Graphic Jump Location

RAS indicates renin-angiotensin system.

Table Graphic Jump LocationTable 3. All-Cause Mortality by Renin-Angiotensin System (RAS) Antagonist Use

In the matched HFPEF cohort, 1-year survival was 77% (95% CI, 75%-78%) for treated patients vs 72% (95% CI, 70%-73%) for untreated patients. Five-year survival was 36% (95% CI, 34%-38%) vs 34% (95% CI, 32%-37%) (Figure 2). The HR was 0.91 (95% CI, 0.85-0.98; P = .008). In the overall cohort adjusted for propensity score, the HR was 0.90 (95% CI, 0.85-0.96, P = .001).

Figure 3 and Figure 4 show the HRs associated with RAS antagonists in the matched cohort for clinically relevant subgroups. Use of RAS antagonists interacted significantly only with mean blood pressure. There was no interaction with ejection fraction (P = .12), but the HRs were nominally different in patients with ejection fractions of 40% to 49% (HR, 0.85 [95% CI, 0.76-0.95]; P = .004) vs patients with ejection fractions of 50% or greater (HR, 0.95 [95% CI, 0.87-1.04]; P = .26).

Place holder to copy figure label and caption
Figure 3. All-Cause Mortality for Patients Treated With Renin-Angiotensin System (RAS) Antagonists vs Untreated Patients in the Matched Cohort
Graphic Jump Location

Squares represent the hazard ratio and the lines represent the 95% confidence interval. Continuous variables were dichotomized at clinically relevant cutoffs.

Place holder to copy figure label and caption
Figure 4. All-Cause Mortality for Patients Treated With Renin-Angiotensin System (RAS) Antagonists vs Untreated Patients in the Matched Cohort
Graphic Jump Location

Squares represent the hazard ratio and the lines represent the 95% confidence interval. Continuous variables were dichotomized at clinically relevant cutoffs. Diabetes is grouped in more detail in Table 2, but dichotomized here for simplicity.

Consistency Analyses

eTables 1-2 show quantified effects of hypothetical confounders in the matched cohort. To invalidate our findings (ie, for RAS antagonists not to be significantly associated with reduced mortality), a binary confounder with a HR for mortality of 1.1 would have to be present in at least 40% (absolute) more in untreated patients vs treated patients. A normally distributed continuous confounder would have to be at least 2 units higher in untreated patients and be associated with a HR of at least 1.03 per unit increase.

In the analysis of propensity for dose-matched HFPEF, 1-year survival was 82% (95% CI, 80%-83%) for high dose, 80% (95% CI, 78%-81%) for low dose, and 76% (95% CI, 75%-78%) for no treatment; and 5-year survival was 43% (95% CI, 40%-46%), 39% (95% CI, 36%-42%), and 40% (95% CI, 37%-42%), respectively (eFigure 2, matched cohort). The HR was 0.85 (95% CI, 0.78-0.83) for high dose vs no treatment (P < .001) and 0.94 (95% CI, 0.87-1.02) for low dose vs no treatment (P = .14; Table 3).

In the analysis of propensity for treatment-matched HFREF, 1-year survival was 67% (95% CI, 64%-69%) for patients receiving RAS antagonists vs 58% (95% CI, 56%-60%) for patients not receiving RAS antagonists; and 5-year survival was 29% (95% CI, 26%-32%) vs 23% (95% CI, 21%-26%), respectively (eFigure 3, matched cohort) (HR, 0.80 [95% CI, 0.74-0.86]; P < .001; Table 3).

In this large, prospective registry of unselected patients with HFPEF, use of RAS antagonists was associated with reduced all-cause mortality. Our findings were consistent, with narrow confidence intervals, in a cohort matched based on age and propensity score and in the overall cohort after adjustment for propensity score. Our findings were strengthened by a positive dose-response relationship and by a separate analysis in patients with HFREF, in which the associated mortality reduction was consistent with published data.

The 77% rate of patients receiving RAS antagonists was as high as the overall population (including patients with HFREF) in our registry,15 and higher than the 44% to 62% rate in patients with HFPEF and similar to the 75% to 82% rate in patients with HFREF in large surveys.2,3 In the unadjusted analysis, there was a large separation between the survival curves and use of RAS antagonists associated with an HR for death of only 0.48. Because treated patients were younger and had better renal function, this benefit was attenuated after adjustment for age or creatinine clearance alone, and because treated patients were healthier in other regards, the benefit was further attenuated but remained significant and consistent in the matched cohort (HR 0.91; 95% CI, 0.85-0.98) and in the overall cohort after adjustment for propensity scores (HR 0.90; 95% CI, 0.85-0.96). Furthermore, in the matched cohort, the mean age was 79 years and the mean creatinine clearance was 52 to 53 mL/min, with a similar benefit to the overall cohort. There was no interaction with age or creatinine clearance, suggesting that age or renal insufficiency alone should not be contraindications to use of RAS antagonists.

Comparison With Previous RCTs

Our findings differ from those of 3 previous RCTs: CHARM preserved,11 PEP-CHF,12 and Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE).13 However, 3 observations suggest that RAS antagonists may nevertheless be beneficial in patients with HFPEF: (1) signals toward benefit in these RCTs, (2) potential selection bias and underpowering in these RCTs; and (3) potentially more severe heart failure and a more unselected and representative population in our study.

In the CHARM preserved study, candesartan did not reduce the primary end point (cardiovascular death or hospitalization for heart failure) but covariate-adjusted hospitalization for heart failure was reduced. In the CHARM overall study, the covariate-adjusted primary end point (all-cause mortality) was reduced without heterogeneity across the component trials, including the CHARM preserved study.10 In the PEP-CHF study, there was a nominally large and borderline significant benefit in the primary end point at 1 year, but 26% of patients randomized to the placebo group crossed over to open-label treatment with an ACE inhibitor and the benefit was not sustained. In the I-PRESERVE study, irbesartan was not beneficial but the authors suggested underpowering, citing a 34% drug discontinuation and a 40% concomitant use of ACE inhibitors. In a meta-analysis of these trials, the reduction in combined cardiovascular mortality and hospitalization for heart failure reached significance,28 confirming the hypothesis made by us and others14 that the individual trials were underpowered. Another meta-analysis suggested reduced all-cause mortality.29 In a previous study from our registry, candesartan was associated with lower mortality than losartan, potentially due to greater angiotensin II receptor antagonism and supporting the role of RAS antagonists in patients with HFPEF.16

In these RCTs, patients were considerably healthier than in epidemiological surveys and in our study, which is consistent with documented systematic selection bias and poor generalizability in RCTs.30 Mean or median age ranged from 67 to 75 years, with a majority having a New York Heart Association classification of I or II, only 17% to 30% had atrial fibrillation, with mean or median renal function near normal, and significant renal insufficiency as exclusion criterion. In contrast, in our matched cohort, mean age was 79 years, most had a New York Heart Association classification of II or III, more than 50% had atrial fibrillation and mean creatinine clearance was 52 to 53 mL/min.

In the RCTs, patients also had milder heart failure and possibly no heart failure at all. Median N-terminal pro-brain natriuretic peptide level was only 335 to 453 pg/mL in the PEP-CHF study and 320 to 360 pg/mL in the I-PRESERVE study compared with 2464 to 2522 pg/mL in our study. The European Society of Cardiology guidelines suggest that N-terminal pro-brain natriuretic peptide level of less than 300 pg/mL makes heart failure unlikely.31 N-terminal pro-brain natriuretic peptide is proportional to the severity of heart failure.32 In the I-PRESERVE study, 80% had a New York Heart Association classification of III to IV, surprisingly severe for such a low N-terminal pro-brain natriuretic peptide level and suggesting other reasons than heart failure for poor functional status and prognosis.

In the RCTs, healthier patients may also explain the low outcome rates, leading to underpowering. In the CHARM preserved study, only 11% in both groups experienced cardiovascular death over 37 months. In the PEP-CHF study at 1 year, only 4.0% vs 4.5% died. In the I-PRESERVE study, 11% died in both groups over 49.5 months. This is in stark contrast to epidemiological surveys with rates of approximately 25% for 1-year mortality and 60% for 5-year mortality. In our study, 1-year mortality ranged from 11% to 31% and 5-year mortality ranged from 39% to 68%, depending on cohort and treatment. In addition, the close monitoring and specialist follow-up in RCTs may dilute the benefits of RAS antagonists, contributing to underpowering, whereas in our study, a majority of patients were cared for by an internal medicine physician or a geriatrician and follow-up referral was to primary care in half of the patients.

Although our study may be more representative and generalizable than the RCTs, patients excluded due to unknown ejection fraction or treatment with RAS antagonist were (as expected) older, more frequently women, and overall less healthy. This suggests that even in our less selective registry, we cannot completely eliminate the selection bias and limited generalizability that may occur in RCTs.30

Consistency Analyses

Observational studies are subject to confounding and may exaggerate benefits seen in RCTs.2224 Therefore, we performed a dose-response analysis in the HFPEF cohort and a positive-control consistency analysis in patients with HFREF. Specific dosing trials suggest greater benefit with higher dose in patients with HFREF.26,27 In our HFPEF cohort, we observed a proportional associated reduction in mortality with doses of 50% or greater of target vs less than 50% of target vs no treatment, suggesting patients with HFPEF may respond similarly to patients with HFREF.

In our HFREF analysis, the HR for mortality of 0.80 (ie, 20% reduction in mortality) was similar to previous RCTs and precisely matches that seen in a large meta-analysis in HFREF,9 confirming that our registry and findings are representative of other rigorous settings.

The HR range of 0.90 to 0.91 in patients with HFPEF represents a lower reduction in all-cause mortality than in patients with HFREF. This may reflect a lower degree of RAS and aldosterone activation in patients with HFPEF,6 lower all-cause2,3 or cardiovascular33 mortality in patients with HFPEF, or higher age, comorbidity, and noncardiovascular mortality in patients with HFPEF,20,21,33 which is less likely to be prevented by RAS antagonists.

While the prognosis in patients with HFPEF may be similar20,21 or better2,3 than in patients with HFREF, once ejection fraction is above 40%, it does not affect prognosis further.2,34 In the HFPEF cohort, there was no heterogeneity with regard to ejection fraction, but the nominal benefit of RAS antagonists was greater in patients with ejection fractions of 40% to 49% than in those with ejection fractions of 50% or greater. Together with the yet greater benefit in our HFREF cohort and other HFREF studies,9 this suggests that heart failure may be on a continuous ejection fraction spectrum, with greater benefit of RAS antagonists the lower the ejection fraction. Currently, RAS antagonists are recommended only in patients with ejection fractions of less than 40%.31 Even though ejection fractions of 40% to 49% may not be considered normal, the benefit in this group has not previously been demonstrated.

Limitations

In the hierarchy of strengths of evidence, RCTs are superior to observational studies.2224 An observational registry study is subject to confounding.24 Our study contains matching and propensity score adjustment for most variables that we are aware may affect the choice to prescribe a RAS antagonist (bias) and to affect outcome independent of RAS antagonist (confounding). However, we cannot rule out residual confounding from unknown or unmeasured variables.24 To invalidate our findings, such confounding would have to be of reasonable magnitude, associated with mortality independently of all variables measured in our study and independently of treatment, and likely to affect the choice to prescribe a RAS antagonist. Although RCTs eliminate bias and confounding, they may have limited generalizability and may be complemented by rigorous registry studies with greater power.22,24

As in the RCTs discussed,1113 heart failure was a clinical diagnosis, and although median N-terminal pro-brain natriuretic peptide level was high, we cannot be completely sure that all patients had heart failure. Dosing of RAS antagonists was suboptimal, but we observed a dose response. Treatment may have changed over time, but this should, if anything, underestimate the true benefit. We assessed all-cause mortality but not cause of death, hospitalization, or cause of hospitalization. In the 3 RCTs, mortality in both treated and untreated patients with HFPEF was mainly cardiovascular.12,35,36 The relative effect of RAS antagonists on all-cause mortality vs cardiovascular mortality remains to be determined. One potential explanation for the benefits of RAS antagonists may be blood pressure lowering, as seen in studies not on heart failure.37,38 In our study, there was a significant interaction yielding a greater benefit with use of RAS antagonists and lower mean blood pressure. Although this may be due to chance, it may suggest that RAS antagonists are more effective in sicker patients (eg, those with lower blood pressure and ejection fraction).

There is currently no consensus on the use of RAS antagonists in patients with HFPEF. In our study, use of RAS antagonists was associated with reduced all-cause mortality in a broad unselected population of patients with HFPEF. Our results together with the signal toward benefit in RCTs suggest that RAS antagonists may be beneficial in patients with HFPEF, but this should be confirmed in an appropriately powered randomized trial.

Corresponding Author: Lars H. Lund, MD, PhD, Section for Heart Failure, Karolinska University Hospital, N305, 171 76 Stockholm, Sweden (lars.lund@alumni.duke.edu).

Author Contributions: Dr Lund had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Lund, Dahlström, Edner.

Acquisition of data: Lund.

Analysis and interpretation of data: Lund, Benson, Dahlström, Edner.

Drafting of the manuscript: Lund.

Critical revision of the manuscript for important intellectual content: Lund, Benson, Dahlström, Edner.

Statistical analysis: Lund, Benson.

Obtained funding: Lund.

Administrative, technical, or material support: Lund.

Study supervision: Lund.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lund reported receiving institutional research grants and speaker's and consulting fees from AstraZeneca, Thoratec, and HeartWare. No other disclosures were reported.

Funding/Support: The Swedish Heart Failure Registry is funded by the Swedish National Board of Health and Welfare, the Swedish Association of Local Authorities and Regions, the Swedish Society of Cardiology, and the Swedish Heart-Lung Foundation. This study received no specific funding. Dr Lund was supported by grants 20080409 and 20100419 from the Swedish Heart-Lung Foundation, grants 00556-2009 and 20110120 from the Stockholm County Council, and an unrestricted research grant from AstraZeneca.

Role of the Sponsor: No funding agency had any role in the design and conduct of the study, in the collection, management, analysis, or interpretation of the data, or in the preparation, review, or approval of the manuscript.

Additional Contributions: We thank all local center study personnel for data collection and entry.

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Eklind-Cervenka M, Benson L, Dahlström U, Edner M, Rosenqvist M, Lund LH. Association of candesartan vs losartan with all-cause mortality in patients with heart failure.  JAMA. 2011;305(2):175-182
PubMed   |  Link to Article
Rosenbaum PR, Rubin DB. Reducing bias in observational studies using subclassification on the propensity score.  J Am Stat Assoc. 1984;79(387):516-524
Link to Article
D’Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group.  Stat Med. 1998;17(19):2265-2281
PubMed   |  Link to Article
Sekhon JS. Multivariate and propensity score matching software with automated balance optimization: the matching package for R.  J Stat Softw. 2011;42(7):1-52
Bhatia RS, Tu JV, Lee DS,  et al.  Outcome of heart failure with preserved ejection fraction in a population-based study.  N Engl J Med. 2006;355(3):260-269
PubMed   |  Link to Article
Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction.  N Engl J Med. 2006;355(3):251-259
PubMed   |  Link to Article
Guyatt GH, Haynes RB, Jaeschke RZ,  et al; Evidence-Based Medicine Working Group.  Users' Guides to the Medical Literature, XXV: evidence-based medicine: principles for applying the users' guides to patient care.  JAMA. 2000;284(10):1290-1296
PubMed   |  Link to Article
Shah NR. What is the best evidence for making clinical decisions?  JAMA. 2000;284(24):3127-3128
PubMed   |  Link to Article
Guyatt G. Users' Guides to the Medical Literature: Essentials of Evidence-Based Clinical Practice.  2nd ed. New York, NY: McGraw-Hill Medical; 2008
Lin DY, Psaty BM, Kronmal RA. Assessing the sensitivity of regression results to unmeasured confounders in observational studies.  Biometrics. 1998;54(3):948-963
PubMed   |  Link to Article
Packer M, Poole-Wilson PA, Armstrong PW,  et al; ATLAS Study Group.  Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure.  Circulation. 1999;100(23):2312-2318
PubMed   |  Link to Article
Konstam MA, Neaton JD, Dickstein K,  et al; HEAAL Investigators.  Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.  Lancet. 2009;374(9704):1840-1848
PubMed   |  Link to Article
Meune C, Wahbi K, Duboc D, Weber S. Meta-analysis of renin-angiotensin-aldosterone blockade for heart failure in presence of preserved left ventricular function.  J Cardiovasc Pharmacol Ther. 2011;16(3-4):368-375
PubMed   |  Link to Article
Fu M, Zhou J, Sun A,  et al.  Efficacy of ACE inhibitors in chronic heart failure with preserved ejection fraction: a meta analysis of 7 prospective clinical studies.  Int J Cardiol. 2012;155(1):33-38
PubMed   |  Link to Article
Van Spall HG, Toren A, Kiss A, Fowler RA. Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review.  JAMA. 2007;297(11):1233-1240
PubMed   |  Link to Article
McMurray JJ, Adamopoulos S, Anker SD,  et al; ESC Committee for Practice Guidelines.  ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology: developed in collaboration with the Heart Failure Association (HFA) of the ESC.  Eur Heart J. 2012;33(14):1787-1847
PubMed   |  Link to Article
Daniels LB, Maisel AS. Natriuretic peptides.  J Am Coll Cardiol. 2007;50(25):2357-2368
PubMed   |  Link to Article
Henkel DM, Redfield MM, Weston SA, Gerber Y, Roger VL. Death in heart failure: a community perspective.  Circ Heart Fail. 2008;1(2):91-97
PubMed   |  Link to Article
Solomon SD, Anavekar N, Skali H,  et al; Candesartan in Heart Failure Reduction in Mortality (CHARM) Investigators.  Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients.  Circulation. 2005;112(24):3738-3744
PubMed   |  Link to Article
Solomon SD, Wang D, Finn P,  et al.  Effect of candesartan on cause-specific mortality in heart failure patients: the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program.  Circulation. 2004;110(15):2180-2183
PubMed   |  Link to Article
Zile MR, Gaasch WH, Anand IS,  et al; I-Preserve Investigators.  Mode of death in patients with heart failure and a preserved ejection fraction: results from the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) trial.  Circulation. 2010;121(12):1393-1405
PubMed   |  Link to Article
Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G.The Heart Outcomes Prevention Evaluation Study Investigators.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.  N Engl J Med. 2000;342(3):145-153
PubMed   |  Link to Article
Fox KM.EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators.  Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).  Lancet. 2003;362(9386):782-788
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Distribution of Propensity Scores in the Matched and Overall Cohorts
Graphic Jump Location

Boxes represent median and interquartile range; whiskers represent minimum and maximum (if not outliers). Outliers are displayed with circles and are defined as observations more than 1.5 times the interquartile range from the first or third quartile, respectively. RAS indicates renin-angiotensin system.

Place holder to copy figure label and caption
Figure 2. Kaplan-Meier Survival Curves in the Matched and Overall Cohorts
Graphic Jump Location

RAS indicates renin-angiotensin system.

Place holder to copy figure label and caption
Figure 3. All-Cause Mortality for Patients Treated With Renin-Angiotensin System (RAS) Antagonists vs Untreated Patients in the Matched Cohort
Graphic Jump Location

Squares represent the hazard ratio and the lines represent the 95% confidence interval. Continuous variables were dichotomized at clinically relevant cutoffs.

Place holder to copy figure label and caption
Figure 4. All-Cause Mortality for Patients Treated With Renin-Angiotensin System (RAS) Antagonists vs Untreated Patients in the Matched Cohort
Graphic Jump Location

Squares represent the hazard ratio and the lines represent the 95% confidence interval. Continuous variables were dichotomized at clinically relevant cutoffs. Diabetes is grouped in more detail in Table 2, but dichotomized here for simplicity.

Tables

Table Graphic Jump LocationTable 1. Characteristics of the Overall and Matched Cohorts and the Standardized Differences Between the Treatment Groupsa
Table Graphic Jump LocationTable 2. Medical History, Medications, and History of Interventions for the Overall and Matched Cohorts and the Standardized Differences Between the Treatment Groupsa
Table Graphic Jump LocationTable 3. All-Cause Mortality by Renin-Angiotensin System (RAS) Antagonist Use

References

Steinberg BA, Zhao X, Heidenreich PA,  et al; Get With the Guidelines Scientific Advisory Committee and Investigators.  Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes.  Circulation. 2012;126(1):65-75
PubMed   |  Link to Article
Meta-analysis Global Group in Chronic Heart Failure (MAGGIC).  The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis.  Eur Heart J. 2012;33(14):1750-1757
PubMed   |  Link to Article
Lenzen MJ, Scholte op Reimer WJ, Boersma E,  et al.  Differences between patients with a preserved and a depressed left ventricular function: a report from the EuroHeart Failure Survey.  Eur Heart J. 2004;25(14):1214-1220
PubMed   |  Link to Article
Kitzman DW, Little WC, Brubaker PH,  et al.  Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure.  JAMA. 2002;288(17):2144-2150
PubMed   |  Link to Article
Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.  JAMA. 2003;289(2):194-202
PubMed   |  Link to Article
Hogg K, McMurray J. Neurohumoral pathways in heart failure with preserved systolic function.  Prog Cardiovasc Dis. 2005;47(6):357-366
PubMed   |  Link to Article
Desai A. Current understanding of heart failure with preserved ejection fraction.  Curr Opin Cardiol. 2007;22(6):578-585
PubMed   |  Link to Article
Wright JW, Mizutani S, Harding JW. Pathways involved in the transition from hypertension to hypertrophy to heart failure: treatment strategies.  Heart Fail Rev. 2008;13(3):367-375
PubMed   |  Link to Article
Flather MD, Yusuf S, Køber L,  et al; ACE-Inhibitor Myocardial Infarction Collaborative Group.  Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients.  Lancet. 2000;355(9215):1575-1581
PubMed   |  Link to Article
Pfeffer MA, Swedberg K, Granger CB,  et al; CHARM Investigators and Committees.  Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-overall programme.  Lancet. 2003;362(9386):759-766
PubMed   |  Link to Article
Yusuf S, Pfeffer MA, Swedberg K,  et al; CHARM Investigators and Committees.  Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-preserved trial.  Lancet. 2003;362(9386):777-781
PubMed   |  Link to Article
Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J.PEP-CHF Investigators.  The perindopril in elderly people with chronic heart failure (PEP-CHF) study.  Eur Heart J. 2006;27(19):2338-2345
PubMed   |  Link to Article
Massie BM, Carson PE, McMurray JJ,  et al; I-PRESERVE Investigators.  Irbesartan in patients with heart failure and preserved ejection fraction.  N Engl J Med. 2008;359(23):2456-2467
PubMed   |  Link to Article
McMurray J. Renin angiotensin blockade in heart failure with preserved ejection fraction: the signal gets stronger.  Eur Heart J. 2006;27(19):2257-2259
PubMed   |  Link to Article
Jonsson A, Edner M, Alehagen U, Dahlström U. Heart failure registry: a valuable tool for improving the management of patients with heart failure.  Eur J Heart Fail. 2010;12(1):25-31
PubMed   |  Link to Article
Eklind-Cervenka M, Benson L, Dahlström U, Edner M, Rosenqvist M, Lund LH. Association of candesartan vs losartan with all-cause mortality in patients with heart failure.  JAMA. 2011;305(2):175-182
PubMed   |  Link to Article
Rosenbaum PR, Rubin DB. Reducing bias in observational studies using subclassification on the propensity score.  J Am Stat Assoc. 1984;79(387):516-524
Link to Article
D’Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group.  Stat Med. 1998;17(19):2265-2281
PubMed   |  Link to Article
Sekhon JS. Multivariate and propensity score matching software with automated balance optimization: the matching package for R.  J Stat Softw. 2011;42(7):1-52
Bhatia RS, Tu JV, Lee DS,  et al.  Outcome of heart failure with preserved ejection fraction in a population-based study.  N Engl J Med. 2006;355(3):260-269
PubMed   |  Link to Article
Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction.  N Engl J Med. 2006;355(3):251-259
PubMed   |  Link to Article
Guyatt GH, Haynes RB, Jaeschke RZ,  et al; Evidence-Based Medicine Working Group.  Users' Guides to the Medical Literature, XXV: evidence-based medicine: principles for applying the users' guides to patient care.  JAMA. 2000;284(10):1290-1296
PubMed   |  Link to Article
Shah NR. What is the best evidence for making clinical decisions?  JAMA. 2000;284(24):3127-3128
PubMed   |  Link to Article
Guyatt G. Users' Guides to the Medical Literature: Essentials of Evidence-Based Clinical Practice.  2nd ed. New York, NY: McGraw-Hill Medical; 2008
Lin DY, Psaty BM, Kronmal RA. Assessing the sensitivity of regression results to unmeasured confounders in observational studies.  Biometrics. 1998;54(3):948-963
PubMed   |  Link to Article
Packer M, Poole-Wilson PA, Armstrong PW,  et al; ATLAS Study Group.  Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure.  Circulation. 1999;100(23):2312-2318
PubMed   |  Link to Article
Konstam MA, Neaton JD, Dickstein K,  et al; HEAAL Investigators.  Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.  Lancet. 2009;374(9704):1840-1848
PubMed   |  Link to Article
Meune C, Wahbi K, Duboc D, Weber S. Meta-analysis of renin-angiotensin-aldosterone blockade for heart failure in presence of preserved left ventricular function.  J Cardiovasc Pharmacol Ther. 2011;16(3-4):368-375
PubMed   |  Link to Article
Fu M, Zhou J, Sun A,  et al.  Efficacy of ACE inhibitors in chronic heart failure with preserved ejection fraction: a meta analysis of 7 prospective clinical studies.  Int J Cardiol. 2012;155(1):33-38
PubMed   |  Link to Article
Van Spall HG, Toren A, Kiss A, Fowler RA. Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review.  JAMA. 2007;297(11):1233-1240
PubMed   |  Link to Article
McMurray JJ, Adamopoulos S, Anker SD,  et al; ESC Committee for Practice Guidelines.  ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology: developed in collaboration with the Heart Failure Association (HFA) of the ESC.  Eur Heart J. 2012;33(14):1787-1847
PubMed   |  Link to Article
Daniels LB, Maisel AS. Natriuretic peptides.  J Am Coll Cardiol. 2007;50(25):2357-2368
PubMed   |  Link to Article
Henkel DM, Redfield MM, Weston SA, Gerber Y, Roger VL. Death in heart failure: a community perspective.  Circ Heart Fail. 2008;1(2):91-97
PubMed   |  Link to Article
Solomon SD, Anavekar N, Skali H,  et al; Candesartan in Heart Failure Reduction in Mortality (CHARM) Investigators.  Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients.  Circulation. 2005;112(24):3738-3744
PubMed   |  Link to Article
Solomon SD, Wang D, Finn P,  et al.  Effect of candesartan on cause-specific mortality in heart failure patients: the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program.  Circulation. 2004;110(15):2180-2183
PubMed   |  Link to Article
Zile MR, Gaasch WH, Anand IS,  et al; I-Preserve Investigators.  Mode of death in patients with heart failure and a preserved ejection fraction: results from the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) trial.  Circulation. 2010;121(12):1393-1405
PubMed   |  Link to Article
Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G.The Heart Outcomes Prevention Evaluation Study Investigators.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.  N Engl J Med. 2000;342(3):145-153
PubMed   |  Link to Article
Fox KM.EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators.  Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).  Lancet. 2003;362(9386):782-788
PubMed   |  Link to Article
March 20, 2013
Gregg C. Fonarow, MD; Ali Ahmed, MD
JAMA. 2013;309(11):1107-1108. doi:10.1001/jama.2013.1969.
March 20, 2013
Lars H. Lund, MD, PhD; Lina Benson, MSc
JAMA. 2013;309(11):1107-1108. doi:10.1001/jama.2013.1975.
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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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Multimedia

Supplemental Content

Lund LH, Benson L, Dahlström U, Edner M. Association between use of reninangiotensin system antagonists and mortality in patients with heart failure and preserved ejection fraction. JAMA. doi:10.1001/jama.2012.14785

eTable 1. Binary confounder with a hazard ratio for mortality of 1.1

eTable 2. Normally distributed continuous confounder

eTable 3. Specific RAS-antagonist agents and doses in HFPEF

eTable 4. Comparison on included HFPEF patients vs. exluded patients

eTable 5. Comparison of all included (HFPEF+HFREF) patients vs. exluded patients

eFigure 1. Patient flow chart

eFigure 2. For the HFPEF population, Kaplan-Meier survival according to treatment and dose (= 50% of target dose, < 50% of target dose, and no treatment), in the matched and total cohorts

eFigure 3. Separate survival analysis in the HFREF population (n = 20,111); Kaplan- Meier survival in the matched and total cohorts

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