Su E Yeoh

Pooja Dewan

João Matteo Serenelli

Pedro Ferreira

Bertram Pitt

Karl Swedberg

Dirk J Veldhuisen

Faiez Zannad

Pardeep S Jhund

John J V Mcmurray
email: john.mcmurray@glasgow.ac.uk

João Pedro Ferreira

Dirk J Van Veldhuisen

Effects of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction patients with chronic obstructive pulmonary disease in EMPHASIS-HF and RALES

Keywords: Heart failure, Mineralocorticoid receptor antagonists, Chronic obstructive pulmonary disease

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Chronic obstructive pulmonary disease (COPD) is more common in patients with heart failure and reduced ejection fraction (HFrEF) than in the general population because each condition can arise as a complication of smoking. [START_REF] Hawkins | Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology[END_REF][START_REF] Güder | Comorbidity of heart failure and chronic obstructive pulmonary disease: more than coincidence[END_REF][START_REF] Jaiswal | Challenges in the management of patients with chronic obstructive pulmonary disease and heart failure with reduced ejection fraction[END_REF][START_REF] Horodinschi | Heart failure and chronic obstructive pulmonary disease: a review[END_REF][START_REF] Pellicori | Chronic obstructive pulmonary disease and heart failure: a breathless conspiracy[END_REF] Concomitant COPD is associated with even worse symptoms, functional limitation and clinical outcomes than in HFrEF alone. [START_REF] Hawkins | Heart failure and chronic obstructive pulmonary disease: the challenges facing physicians and health services[END_REF][START_REF] Mentz | Clinical characteristics, response to exercise training, and outcomes in patients with heart failure and chronic obstructive pulmonary disease: findings from Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION)[END_REF][START_REF] Tavazzi | Clinical profiles and outcomes in patients with chronic heart failure and chronic obstructive pulmonary disease: an efficacy and safety analysis of SHIFT study[END_REF] Coexisting COPD also creates therapeutic difficulties. Beta-blockers are a key, life-saving treatment for HFrEF, but may not be tolerated in people with COPD, antagonise the effects of beta-2 adrenoceptor agonists, a core therapy for COPD, and can cause exacerbations of COPD. [START_REF] Hawkins | Heart failure and chronic obstructive pulmonary disease: the quandary of beta-blockers and beta-agonists[END_REF] However, many if not most patients with COPD can tolerate a beta-1 selective blocker and this treatment should not be withheld in patients with COPD. Conversely, beta-2 adrenoceptor agonists can cause tachycardia and hypokalaemia, neither of which is desirable in HFrEF. Both hypokalaemia and methylxanthines, another therapy for COPD, can predispose to arrhythmias. Corticosteroids, especially if given orally, cause fluid retention which is undesirable in HFrEF and in COPD, which is itself a sodium-and water-retaining state (although both methylxanthines and systemic corticosteroids are used in a small minority of patients in most countries).

Clearly, it would be ideal to be able to use all other effective therapies for HFrEF in patients with concomitant COPD in view of their heightened risk of adverse outcomes and potential intolerance of beta-blockers. In many ways mineralocorticoid receptor antagonists (MRAs) seem an ideal treatment for patients with both HFrEF and COPD. Each condition is associated with an increase in plasma aldosterone concentration and MRAs should help counter fluid retention, block any adverse effects of exogenous corticosteroids at the mineralocorticoid receptor and mitigate the risk of hypokalaemia with beta-2 agonists. [START_REF] Horodinschi | Heart failure and chronic obstructive pulmonary disease: a review[END_REF][START_REF] Anand | Pathogenesis of congestive state in chronic obstructive pulmonary disease. Studies of body water and sodium, renal function, hemodynamics, and plasma hormones during edema and after recovery[END_REF][START_REF] Stewart | Hormonal, renal, and autonomic nerve factors involved in the excretion of sodium and water during dynamic salt and water loading in hypoxaemic chronic obstructive pulmonary disease[END_REF][START_REF] De Leeuw | Fluid homeostasis in chronic obstructive lung disease[END_REF] In addition, MRAs seem to attenuate pathogenic vascular remodelling in the lungs, and right ventricular failure, in experimental models of pulmonary hypertension. [START_REF] Omidkhoda | Aldosterone and mineralocorticoid receptor antagonists on pulmonary hypertension and right ventricular failure: a review[END_REF][START_REF] Safdar | Spironolactone in pulmonary arterial hypertension: results of a cross-over study[END_REF][START_REF] Wang | Aldosterone contributed to pulmonary arterial hypertension development via stimulating aquaporin expression and pulmonary arterial smooth muscle cells proliferation[END_REF][START_REF] Zelt | Medical therapy for heart failure associated with pulmonary hypertension[END_REF][START_REF] Boehm | Eplerenone attenuates pathological pulmonary vascular rather than right ventricular remodeling in pulmonary arterial hypertension[END_REF] These problems also occur as secondary complications in some patients with COPD. Surprisingly, however, in a large Danish nationwide cohort, use of spironolactone in such patients was associated with a higher mortality than no use of spironolactone, the opposite of what was found for beta-blockers and renin-angiotensin system antagonists. [START_REF] Andersson | Mortality associated with cardiovascular drugs in patients with chronic obstructive pulmonary disease and right-sided heart failure -A Danish nationwide registry-based study[END_REF] While this unexpected finding may reflect the specific characteristics of the Danish patients (all of whom had right heart failure) or unmeasured or uncorrected confounding in an observational cohort, it does suggest the subject merits further investigation. MRAs can cause worsening of kidney function and renal dysfunction is common in both HFrEF and COPD. MRAs can also lead to hyperkalaemia which may lead to ventricular arrhythmias and patients with the combination of HFrEF and COPD may be particularly vulnerable to these. [START_REF] Leong | Coexisting chronic obstructive pulmonary disease and cardiovascular disease in clinical practice: a diagnostic and therapeutic challenge[END_REF][START_REF] Van Den Berg | Chronic obstructive pulmonary disease and sudden cardiac death: a systematic review[END_REF][START_REF] Goudis | Electrocardiographic abnormalities and cardiac arrhythmias in chronic obstructive pulmonary disease[END_REF] Despite the Danish observational data and potential for hyperkalaemia to increase the risk of arrhythmias, our hypothesis was that MRAs would be as beneficial in HFrEF patients with COPD, as in those without. Fortunately, there are prospective randomised controlled trial data which allow us to examine both the efficacy and safety of MRAs in HFrEF patients with concomitant COPD. Therefore, in a post hoc analysis, we examined the effect of MRAs

Methods

RALES and EMPHASIS-HF were each prospective, double-blind, placebo-controlled, event-driven mortality/morbidity trials. Each trial received ethics committee approval and all participants provided written informed consent. Their design, baseline findings, and primary results are published in full. [START_REF] Pitt | The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators[END_REF][START_REF] Zannad | Eplerenone in patients with systolic heart failure and mild symptoms[END_REF][START_REF] Pitt | ACE inhibitor co-therapy in patients with heart failure: rationale for the Randomized Aldactone Evaluation Study (RALES)[END_REF][START_REF] Zannad | Rationale and design of the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF)[END_REF] The mean follow-up in RALES was 24 months and median follow-up in EMPHASIS-HF was 21 months.

Trial patients

In RALES, patients with New York Heart Association (NYHA) functional class III or IV heart failure, a left ventricular ejection fraction (LVEF) of ≤35% and receiving current treatment with an angiotensin-converting enzyme (ACE) inhibitor (if tolerated) and a loop diuretic, were randomly assigned to receive either spironolactone or placebo. In EMPHASIS-HF, patients with NYHA functional class II heart failure, LVEF of ≤30% (or ≤35% if QRS duration >130 ms) and receiving optimal ACE inhibitor/angiotensin receptor blocker (ARB) and beta-blocker therapy (unless contraindicated), were randomly assigned to either eplerenone or placebo. Exclusion criteria are detailed in the design and results papers. [START_REF] Pitt | The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators[END_REF][START_REF] Zannad | Rationale and design of the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF)[END_REF] There was no exclusion related to COPD in either trial, although investigators were asked to exclude patients with another clinically important condition (e.g. cancer) likely to greatly shorten life expectancy.

Trial treatments

In RALES, patients were assigned to a starting dosage of 25 mg of spironolactone once daily or a matching placebo. After 8 weeks, the dose could be increased to 50 mg once daily 'if the patient showed signs or symptoms of progression of heart failure without evidence of hyperkalaemia'. In EMPHASIS-HF, eplerenone was started at a dose of 25 mg once daily and was increased after 4 weeks to 50 mg once daily (or started at 25 mg on alternate days, and increased to 25 mg daily, if the estimated glomerular filtration rate was 30 to 49 mL/min/1.73 m 2 ), provided the serum potassium level was no more than 5.0 mmol/L.

Identification of chronic obstructive pulmonary disease

Diagnosis of COPD was reported by investigators in the medical history section of the case report forms in each of RALES and EMPHASIS-HF. There was a specific 'yes or no' question about COPD, but no specific criteria were provided for a diagnosis of COPD.

Study outcomes

The primary outcome in RALES was death from any cause and in EMPHASIS-HF it was time to first occurrence of heart failure hospitalisation or death from a cardiovascular cause. The latter was used as the primary endpoint in the present analysis. We also examined the components of this composite, non-cardiovascular and all-cause death, as well as pump failure and sudden cardiac death.

Statistical analysis

In order to maximise the number of COPD patients and events, as well as cover the full spectrum of heart failure symptom severity (NYHA class II to IV), we merged the RALES and EMPHASIS-HF databases. Certain baseline data were collected in EMPHASIS-HF, but not RALES. Hence, the baseline analysis is presented in two tables: Table 1 (baseline characteristics collected in both RALES and EMPHASIS-HF) and online supplementary Table S1 (additional baseline data collected in EMPHASIS-HF only). Baseline characteristics are reported as means and standard deviations for continuous variables and frequencies with percentages for categorical variables. Time-to-event endpoints were evaluated using Kaplan-Meier estimates and Cox proportional hazard models, stratified according to trial and adjusted for randomised treatment group to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Along with crude HRs, we also report HRs adjusted for age, sex, race, heart rate, systolic blood pressure, NYHA classification, LVEF, estimated glomerular filtration rate, history of myocardial infarction, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . diabetes and atrial fibrillation. In a sensitivity analysis, we also adjusted for beta-blocker use at baseline, given the anticipated imbalance in the use of these drugs between patients with and without COPD and their powerful effect of clinical outcomes in HFrEF.

The treatment effect for each time-to-event endpoint was estimated using Cox models with an interaction term between baseline COPD status and treatment group. The interaction between COPD status and effect of randomised treatment on adverse events and study drug discontinuation was analysed using a logistic regression model with an interaction term between baseline COPD status and treatment.

A P-value of < 0.05 was considered significant. Statistical analyses were conducted using STATA version 16.0 (Stata Corp., College Station, TX, USA).

Results

Overall, 4397 patients were included in the analysis, of whom 2212 were randomised to placebo and 2185 to an MRA. Of the included patients, 625 (14.2%) had COPD: 321 (14.7%) in the MRA group and 304 (13.7%) in the placebo group.

Baseline characteristics according to chronic obstructive pulmonary disease status

The baseline characteristics of patients in the combined RALES and EMPHASIS-HF dataset are shown in Table 1 according to COPD status. Patients with COPD were older and more often men. They were also more likely than patients without COPD to have a history of hypertension, atrial fibrillation and stroke but not of coronary heart disease. NYHA functional class distribution, LVEF and kidney function were similar in each COPD subgroup.

Patients with COPD were significantly less likely to be treated with a beta-blocker. Data on beta-blocker selectivity were not available.

Online supplementary Table S1 contains additional data collected in EMPHASIS-HF only. In EMPHASIS-HF, patients with COPD were more often current smokers (21.7%) than those without COPD (8.9%).

Clinical outcomes according to chronic obstructive pulmonary disease status

The incidence rate (per 100 person-years) and unadjusted risk of most outcomes examined were higher in patients with COPD compared to those without (the exception was pump failure death, although numbers of this event in the COPD groups were small). The elevated risks were attenuated by multivariable adjustment (Table 2).

Primary outcome (composite of heart failure hospitalisation or cardiovascular death)

The event rates were 25.2 (95% CI 22.1-28.7) in patients with COPD, vs. 19.9 (95% CI 18.8-21.1) in those without COPD with unadjusted HR 1.25 (95% CI 1.08-1.44), using patients without COPD as the reference group (Figure 1). The elevated risk was attenuated to HR 1.16 (95% CI 1.00-1.35) after adjustment for standard prognostic variables. A similar picture was seen for the components of the composite outcome.

Mortality

The higher rate of cardiovascular mortality in patients with COPD was driven by an elevated risk of sudden death compared with pump failure death, compared to patients without COPD: unadjusted HR 1.44 (95% CI 1.09-1.91) for sudden death vs. 1.14 (95% CI 0.88-1.49) for pump failure death.

The rate of non-cardiovascular mortality, and therefore all-cause mortality, was also higher in patients with COPD, with a greater elevation in risk of non-cardiovascular death vs. cardiovascular death, compared to participants without COPD [unadjusted HR 1.82 (95% CI 1.28-2.58) for non-cardiovascular death vs. 1.25 (95% CI 1.04-1.49) for cardiovascular death] (Figure 1 Examination of causes of non-cardiovascular deaths showed an excess of deaths due to infection/sepsis in patients with COPD compared to those without COPD (online supplementary Figure S1).

Hospitalisations

Patients with COPD had higher all-cause, heart failure and non-cardiovascular hospitalisations [unadjusted HR 1.33 (95% CI 1.17-1.51), 1.25 (95% CI 1.05-1.49) and 1.79 (95% CI 1.44-2.22), respectively]. In contrast to heart failure hospitalisations, the elevated risk of all-cause and non-cardiovascular hospitalisations persisted with multivariable adjustment.

In the sensitivity analyses, further adjusting for beta-blocker slightly attenuated the excess risk related to COPD, more so for heart failure hospitalisation than the other outcomes.

These findings were consistent when RALES and EMPHASIS-HF were analysed separately (online supplementary Tables S2 andS3).

Efficacy of mineralocorticoid receptor antagonists according to chronic obstructive pulmonary disease status

The benefits of MRAs, compared with placebo, were consistent in patients with and without COPD for all mortality and hospitalisation outcomes (Table 3 and Figure 1). The HR for the primary outcome was 0.66 (95% CI 0.50-0.85) in patients with COPD and 0.65 (95% CI 0.58-0.73) in patients without COPD (P-value for interaction =0.93). The HR for all-cause mortality was 0.77 (95% CI 0.58-1.03) in patients with COPD and 0.72 (95% CI 0.63-0.82) in patients without COPD (P-value for interaction =0.65) (Figure 1).

These findings were consistent when RALES and EMPHASIS-HF were analysed separately (online supplementary Tables S4 andS5).

Safety of mineralocorticoid receptor antagonists according to chronic obstructive pulmonary disease status

Mild hyperkalaemia (potassium >5.5 mmol/L) was more common on an MRA than on placebo in patients with or without COPD although moderate-to-severe hyperkalaemia (potassium >6.0 mmol/L) appeared to be increased by MRA therapy only in patients without COPD (Table 4).

Discussion

The prevalence of COPD in this combined RALES and EMPHASIS-HF cohort (14.2%) was similar to that reported in other large-scale HFrEF trials including the Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF; prevalence 12.9%), the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF; prevalence 12.3%) and in a 'real-world' study (the European Society of Cardiology long-term registry; prevalence 14.1%). [START_REF] Mcmurray | Angiotensin-neprilysin inhibition versus enalapril in heart failure[END_REF] As expected, patients with COPD in RALES and EMPHASIS-HF were older and more often male than those without COPD, smoked more (in EMPHASIS-HF) and had more hypertension and atrial fibrillation, although not diabetes, coronary artery disease, or chronic kidney disease. [START_REF] Mentz | Clinical characteristics, response to exercise training, and outcomes in patients with heart failure and chronic obstructive pulmonary disease: findings from Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION)[END_REF][START_REF] Tavazzi | Clinical profiles and outcomes in patients with chronic heart failure and chronic obstructive pulmonary disease: an efficacy and safety analysis of SHIFT study[END_REF][START_REF] Staszewsky | Clinical, neurohormonal, and inflammatory markers and overall prognostic role of chronic obstructive pulmonary disease in patients with heart failure: data from the Val-HeFT Heart Failure trial[END_REF][START_REF] Hawkins | Baseline characteristics and outcomes of patients with heart failure receiving bronchodilators in the CHARM programme[END_REF] There was also no difference in LVEF or NYHA class between the two groups. Therefore, it was notable that despite these rather modest differences in . . . . . . . . . . . . . . . . . . . . . recognised prognostic factors, participants with COPD were at considerably higher risk of hospitalisation and death, as has been documented in other studies. As anticipated, some of the excess mortality in patients with COPD was due to non-cardiovascular causes, primarily due to infection/sepsis. Interestingly, however, we found a higher risk of sudden death in patients with COPD, compared with those without. We are not aware of a prior © 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. report of this finding. It suggests the possibility of a proarrhythmic milieu in patients with COPD related, for example, to beta-2 agonist induced hypokalaemia, methylxanthine and digoxin use, and hypoxaemia, as well as loss of the antiarrhythmic protection of beta-blockers. Interestingly, the excess risk of sudden death (and heart failure hospitalisation) was slightly attenuated by adjustment for baseline beta-blocker use. Concomitant right ventricular dysfunction, which is common in patients with COPD, may further elevate the risk of arrhythmias and sudden death. [START_REF] Jaiswal | Challenges in the management of patients with chronic obstructive pulmonary disease and heart failure with reduced ejection fraction[END_REF][START_REF] Horodinschi | Heart failure and chronic obstructive pulmonary disease: a review[END_REF][START_REF] Leong | Coexisting chronic obstructive pulmonary disease and cardiovascular disease in clinical practice: a diagnostic and therapeutic challenge[END_REF][START_REF] Van Den Berg | Chronic obstructive pulmonary disease and sudden cardiac death: a systematic review[END_REF][START_REF] Goudis | Electrocardiographic abnormalities and cardiac arrhythmias in chronic obstructive pulmonary disease[END_REF] Indeed, because some patients with COPD cannot tolerate beta-blockers, it is even more important that other treatments are available and shown to be effective in HFrEF patients with concomitant COPD. In fact, MRAs may be particularly suited to HFrEF patients with COPD. The importance in avoiding hyperkalaemia has already been highlighted. COPD is itself a fluid-retaining state associated with hyperaldosteronism. [START_REF] Horodinschi | Heart failure and chronic obstructive pulmonary disease: a review[END_REF][START_REF] Anand | Pathogenesis of congestive state in chronic obstructive pulmonary disease. Studies of body water and sodium, renal function, hemodynamics, and plasma hormones during edema and after recovery[END_REF][START_REF] Stewart | Hormonal, renal, and autonomic nerve factors involved in the excretion of sodium and water during dynamic salt and water loading in hypoxaemic chronic obstructive pulmonary disease[END_REF][START_REF] De Leeuw | Fluid homeostasis in chronic obstructive lung disease[END_REF] [START_REF] Omidkhoda | Aldosterone and mineralocorticoid receptor antagonists on pulmonary hypertension and right ventricular failure: a review[END_REF][START_REF] Safdar | Spironolactone in pulmonary arterial hypertension: results of a cross-over study[END_REF][START_REF] Wang | Aldosterone contributed to pulmonary arterial hypertension development via stimulating aquaporin expression and pulmonary arterial smooth muscle cells proliferation[END_REF][START_REF] Zelt | Medical therapy for heart failure associated with pulmonary hypertension[END_REF][START_REF] Boehm | Eplerenone attenuates pathological pulmonary vascular rather than right ventricular remodeling in pulmonary arterial hypertension[END_REF] We showed that MRAs have substantial benefits in HFrEF patients with COPD. The proportional risk reductions in all key outcomes were similar to those obtained in HFrEF patients without COPD, with around a 35% relative risk reduction in the primary composite endpoint and a 30% reduction in cardiovascular death. The absolute risk reductions were also large. In both patient subgroups, the number needed to treat to prevent one patient experiencing the primary endpoint was only 10-12 over a median follow-up of approximately 2 years. Our findings appear to refute those of the Danish observational study which reported higher mortality in patients with COPD and right heart failure using spironolactone. While this is likely due to unmeasured or uncorrected confounding in the Danish cohort, the patients in the two studies were different. All patients in RALES and EMPHASIS-HF had HFrEF whereas the patients in the Danish observational study were selected because of a diagnosis of COPD and pulmonary hypertension and treatment with diuretics; approximately 60% had a concomitant diagnosis of heart failure (ejection phenotype not defined). [START_REF] Andersson | Mortality associated with cardiovascular drugs in patients with chronic obstructive pulmonary disease and right-sided heart failure -A Danish nationwide registry-based study[END_REF] Finally, MRA therapy was as well tolerated in patients with COPD, as in those without. While severe hyperkalaemia was more common in placebo-treated patients with COPD, compared to those without COPD, severe hyperkalaemia was significantly less common in MRA-treated patients with COPD, compared to those without COPD, potentially due to the 'protective' effect of chronic respiratory acidosis, metabolic alkalosis, and corticosteroid therapy or beta-agonist treatment, or both.

Use of MRA in patients with HFrEF has been increasing with rates in patients with COPD, compared with no COPD, of 65.6% vs. 71.8% in DAPA-HF (2019), 54.2% vs. 55.8% in PARADIGM-HF (2014) and 57.0% vs. 52.3% in the ESC Long-Term Registry (data collected 2011-13).

Translational outlook

Although the exact reasons why patients with HFrEF and concomitant COPD are at such high risk are unknown, these data show the risk of sudden death is particularly elevated, compared to patients without COPD. This may be an area of additional research into other preventive strategies.

.

Limitations

This study has several limitations. The analyses conducted were not pre-specified. COPD was investigator-reported, COPD severity was not recorded, and we did not know in whom spirometry had been performed. The patients studied were selected for a clinical trial and will differ from those in ordinary every-day practice. Biomarkers and quality of life data were not collected, and smoking status was only documented in EMPHASIS-HF (and not in RALES).

Conclusion

This analysis highlights the importance of MRA therapy in HFrEF patients with COPD. In the RALES and EMPHASIS-HF trials, one-in-seven patients with HFrEF had coexisting COPD. Patients with HFrEF and concomitant COPD had much worse outcomes but the benefit of MRA therapy was consistent across all morbidity and mortality outcomes examined, regardless of COPD status.

©

  2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

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Figure 1

 1 Figure1Kaplan-Meier curves for key outcomes, according to baseline chronic obstructive pulmonary disease (COPD) status and randomised treatment. The primary outcome was the composite of heart failure hospitalisation and death from cardiovascular causes. MRA, mineralocorticoid receptor antagonist.

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  in the RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trials.[START_REF] Pitt | The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators[END_REF][START_REF] Zannad | Eplerenone in patients with systolic heart failure and mild symptoms[END_REF]

in relation to COPD status in patients with HFrEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . enrolled

Table 1 Baseline characteristics according to chronic obstructive pulmonary disease status All patients (n = 4397) a Without COPD (n = 3772) With COPD (n = 625) P-value

 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

	Age (years)	67.4 ± 9.6	67.1 ± 9.8	69.1 ± 7.9	<0.001
	Women	1056 (24.0)	946 (25.1)	110 (17.6)	<0.001
	Race				<0.001
	White	3706 (84.3)	3140 (83.2)	566 (90.6)
	Black	187 (4.3)	178 (4.7)	9 (1.4)
	Asian	347 (7.9)	308 (8.2)	39 (6.2)
	Other	157 (3.6)	146 (3.9)	11 (1.8)
	Heart rate (bpm)	75.2 ± 13.9	74.9 ± 13.8	76.8 ± 13.9	0.001
	SBP (mmHg)	123.4 ± 18.2	123.4 ± 18.3	123.2 ± 17.4	0.80
	DBP (mmHg)	74.6 ± 10.8	74.7 ± 10.7	74.1 ± 11.0	0.16
	Hypertension	2208 (50.2)	1857 (49.2)	351 (56.2)	0.001
	Diabetes	1228 (27.9)	1054 (27.9)	174 (27.8)	0.96
	Myocardial infarction	1852 (42.1)	1571 (41.6)	281 (45.0)	0.12
	Atrial fibrillation/flutter	1026 (23.3)	861 (22.8)	165 (26.4)	0.051
	Ischaemic CVA	248 (5.7)	199 (5.3)	49 (7.9)	0.010
	HF aetiology				0.22
	Ischaemic	2792 (63.6)	2383 (63.2)	409 (65.8)
	Non-ischaemic	1600 (36.4)	1387 (36.8)	213 (34.2)
	NYHA class				0.19
	II	2740 (62.3)	2349 (62.3)	391 (62.6)
	III	1173 (26.7)	1021 (27.1)	152 (24.3)
	IV	483 (11.0)	401 (10.6)	82 (13.1)
	LVEF (%)	25.8 ± 5.6	25.9 ± 5.5	25.6 ± 5.8	0.30
	eGFR (mL/min/1.73 m 2 )	68.6 ± 22.4	68.6 ± 22.4	68.3 ± 22.4	0.74
	eGFR <60 mL/min/1.73 m 2	1702 (38.8)	1460 (38.8)	242 (38.8)	0.97
	Creatinine (mg/dL)	1.2 ± 0.3	1.2 ± 0.3	1.2 ± 0.3	0.24
	Potassium (mmol/L)	4.3 ± 0.4	4.3 ± 0.4	4.3 ± 0.4	0.054
	Diuretic	3826 (87.3)	3283 (87.3)	543 (87.6)	0.83
	ACEi/ARB	4145 (94.6)	3552 (94.4)	593 (95.6)	0.21
	Beta-blocker	2543 (58.0)	2234 (59.4)	309 (49.8)	<0.001
	Digoxin	1955 (44.6)	1680 (44.7)	275 (44.4)	0.89

Data are presented as mean ± standard deviation for continuous measures, and n (%) for categorical measures. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; SBP, systolic blood pressure. a For 4397 patients of the 4400 randomised because COPD status was not recorded in 3 patients.

Table 2 Event rate (per 100 patient-years) and risk of study endpoints according to chronic obstructive pulmonary disease status Without COPD (n = 3772) With COPD (n = 625) P-value

 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

	HF hospitalisation or cardiovascular death
	Events, n (%)	1195 (31.7)	227 (36.3)
	Event rate per 100 patient-years	19.9 (18.8-21.1)	25.2 (22.1-28.7)
	Unadjusted HR	1.00 (ref.)	1.25 (1.08-1.44)	0.002
	Adjusted HR a	1.00 (ref.)	1.16 (1.00-1.35)	0.045
	Adjusted HR b	1.00 (ref.)	1.12 (0.96-1.30)	0.139
	HF hospitalisation
	Events, n (%)	783 (20.8)	150 (24.0)
	Event rate per 100 patient-years	13.1 (12.2-14.0)	16.6 (14.2-19.5)
	Unadjusted HR	1.00 (ref.)	1.25 (1.05-1.49)	0.011
	Adjusted HR a	1.00 (ref.)	1.17 (0.98-1.40)	0.091
	Adjusted HR b	1.00 (ref.)	1.12 (0.93-1.34)	0.225
	All-cause hospitalisation
	Events, n (%)	1510 (40.0)	294 (47.0)
	Event rate per 100 patient-years	29.2 (27.8-30.7)	39.9 (35.6-44.7)
	Unadjusted HR	1.00 (ref.)	1.33 (1.17-1.51)	<0.001
	Adjusted HR a	1.00 (ref.)	1.25 (1.10-1.42)	0.001
	Adjusted HR b	1.00 (ref.)	1.23 (1.08-1.40)	0.002
	Non-cardiovascular hospitalisation
	Events, n (%)	394 (10.4)	105 (16.8)
	Event rate per 100 patient-years	6.8 (6.1-7.5)	12.2 (10.0-14.8)
	Unadjusted HR	1.00 (ref.)	1.79 (1.44-2.22)	<0.001
	Adjusted HR a	1.00 (ref.)	1.68 (1.34-2.10)	<0.001
	Adjusted HR b	1.00 (ref.)	1.69 (1.35-2.12)	<0.001
	Cardiovascular death
	Events, n (%)	729 (19.3)	142 (22.7)
	Event rate per 100 patient-years	10.8 (10.0-11.6)	13.4 (11.4-15.8)
	Unadjusted HR	1.00 (ref.)	1.25 (1.04-1.49)	0.016
	Adjusted HR a	1.00 (ref.)	1.13 (0.93-1.36)	0.211
	Adjusted HR b	1.00 (ref.)	1.10 (0.91-1.32)	0.329
	Non-cardiovascular death
	Events, n (%)	142 (3.8)	40 (6.4)
	Event rate per 100 patient-years	2.1 (1.8-2.5)	3.8 (2.8-5.2)
	Unadjusted HR	1.00 (ref.)	1.82 (1.28-2.58)	0.001
	Adjusted HR a	1.00 (ref.)	1.85 (1.29-2.65)	0.001
	Adjusted HR b	1.00 (ref.)	1.81 (1.26-2.60)	0.001
	All-cause death
	Events, n (%)	871 (23.1)	182 (29.1)
	Event rate per 100 patient-years	12.8 (12.0-13.7)	17.2 (14.9-19.9)
	Unadjusted HR	1.00 (ref.)	1.34 (1.14-1.57)	<0.001
	Adjusted HR a	1.00 (ref.)	1.24 (1.05-1.46)	0.010
	Adjusted HR b	1.00 (ref.)	1.21 (1.03-1.43)	0.024
	Pump failure death
	Events, n (%)	358 (9.5)	64 (10.2)
	Event rate per 100 patient-years	5.3 (4.7-5.8)	6.1 (4.7-7.7)
	Unadjusted HR	1.00 (ref.)	1.14 (0.88-1.49)	0.327
	Adjusted HR a	1.00 (ref.)	0.96 (0.73-1.27)	0.778
	Adjusted HR b	1.00 (ref.)	0.94 (0.71-1.24)	0.656
	Sudden cardiac death
	Events, n (%)	267 (7.1)	60 (9.6)
	Event rate per 100 patient-years	3.9 (3.5-4.4)	5.7 (4.4-7.3)
	Unadjusted HR	1.00 (ref.)	1.44 (1.09-1.91)	0 . 0 11
	Adjusted HR a	1.00 (ref.)	1.35 (1.01-1.80)	0.042
	Adjusted HR b	1.00 (ref.)	1.31 (0.98-1.76)	0.064

COPD, chronic obstructive pulmonary disease; HF, heart failure; HR, hazard ratio. a Model adjusted for age, sex, race, heart rate, systolic blood pressure, New York Heart Association classification, left ventricular ejection fraction, estimated glomerular filtration rate, history of myocardial infarction, diabetes and atrial fibrillation. b Adjusted as for 'a' with additional adjustment for beta-blocker prescription at baseline.

Table 3 Clinical outcomes and treatment effect according to chronic obstructive pulmonary disease status (mineralocorticoid receptor antagonist vs. placebo event rates and hazard ratios with 95% confidence interval) Without COPD With COPD P-value for interaction

 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

		Placebo (n = 1908)	MRA (n = 1864)	Placebo (n = 304)	MRA (n = 321)
	HF hospitalisation or cardiovascular death
	Events, n (%)	700 (36.7)	495 (26.6)	128 (42.1)	99 (30.8)
	Event rate per 100 patient-years	24.4 (22.6-26.2)	15.8 (14.5-17.3)	31.5 (26.5-37.5)	20.0 (16.4-24.3)
	Unadjusted HR	0.65 (0.58-0.73)	0.66 (0.50-0.85)	0.93
	HF hospitalisation
	Events, n (%)	465 (24.4)	318 (17.1)	88 (28.9)	62 (19.3)
	Event rate per 100 patient-years	16.2 (14.8-17.7)	10.2 (9.1-11.4)	21.7 (17.6-26.7)	12.5 (9.8-16.1)
	Unadjusted HR	0.64 (0.55-0.73)	0.59 (0.43-0.82)	0.79
	All-cause hospitalisation
	Events, n (%)	814 (42.7)	696 (37.3)	158 (52.0)	136 (42.4)
	Event rate per 100 patient-years	32.8 (30.6-35.1)	25.9 (24.1-27.9)	48.6 (41.6-56.8)	33.0 (27.9-39.1)
	Unadjusted HR	0.80 (0.72-0.89)	0.71 (0.57-0.90)	0.28
	Non-cardiovascular hospitalisation
	Events, n (%)	185 (9.7)	209 (11.2)	53 (17.4)	52 (16.2)
	Event rate per 100 patient-years	6.5 (5.6-7.5)	7.0 (6.1-8.1)	13.9 (10.6-18.2)	10.8 (8.2-14.2)
	Unadjusted HR	1.06 (0.87-1.30)	0.78 (0.53-1.14)	0.16
	Cardiovascular death
	Events, n (%)	420 (22.0)	309 (16.6)	79 (26.0)	63 (19.6)
	Event rate per 100 patient-years	12.5 (11.4-13.8)	9.0 (8.1-10.1)	16.1 (12.9-20.1)	11.1 (8.7-14.3)
	Unadjusted HR	0.72 (0.62-0.83)	0.72 (0.52-1.00)	1.00
	All-cause death
	Events, n (%)	501 (26.3)	370 (19.8)	98 (32.2)	84 (26.2)
	Event rate per 100 patient-years	15.0 (13.7-16.3)	10.8 (9.7-11.9)	20.0 (16.4-24.3)	14.8 (12.0-18.4)
	Unadjusted HR	0.72 (0.63-0.82)	0.77 (0.58-1.03)	0.65
	Pump failure death
	Events, n (%)	212 (11.1)	146 (7.8)	38 (12.5)	26 (8.1)
	Event rate per 100 patient-years	6.3 (5.5-7.2)	4.3 (3.6-5.0)	7.7 (5.6-10.6)	4.6 (3.1-6.7)
	Unadjusted HR	0.67 (0.54-0.83)	0.61 (0.37-1.01)	0 . 8 0
	Sudden cardiac death
	Events, n (%)	154 (8.1)	113 (6.1)	3 2 ( 10.5)	28 (8.7)
	Event rate per 100 patient-years	4.6 (3.9-5.4)	3.3 (2.7-4.0)	6.5 (4.6-9.2)	4.9 (3.4-7.2)
	Unadjusted HR	0.71 (0.56-0.91)	0.80 (0.48-1.33)	0.73
	COPD, chronic obstructive pulmonary disease; HF, heart failure; HR, hazard ratio; MRA, mineralocorticoid receptor antagonist.

  The harmful effects of hyperaldosteronism in HFrEF are well recognised and aldosterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . may also have detrimental effects in the pulmonary vasculature, which is especially relevant given the propensity of patients with COPD to develop pulmonary hypertension.

Table 4 Adverse effects of interest and permanent study drug discontinuation according to randomised treatment and chronic obstructive pulmonary disease status at baseline Event Without COPD With COPD P-value for interaction

 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

		Placebo	MRA	Placebo	MRA
		(n = 1908)	(n = 1864)	(n = 304)	(n = 321)
	Hypotension
	Events, n (%)	76 (4.0)	86 (4.6)	10 (3.3)	14 (4.4)
	Unadjusted OR	1.17 (0.85-1.60)	1.36 (0.59-3.12)	0.76
	Creatinine ≥2.5 mg/dL
	Events, n (%)	59 (3.1)	83 (4.5)	6 (2.0)	14 (4.4)
	Unadjusted OR	1.47 (1.05-2.08)	2.38 (0.89-6.33)	0.39
	Creatinine ≥3.0 mg/dL
	Events, n (%)	25 (1.3)	32 (1.7)	3 (1.0)	7 (2.2)
	Unadjusted OR	1.32 (0.78-2.24)	2.32 (0.59-9.12)	0.47
	Potassium >5.5 mmol/L
	Events, n (%)	111 (5.8)	244 (13.1)	22 (7.2)	42 (13.1)
	Unadjusted OR	2.44 (1.93-3.08)	1.95 (1.13-3.36)	0.44
	Potassium >6.0 mmol/L
	Events, n (%)	23 (1.2)	60 (3.2)	9 (3.0)	6 (1.9)
	Unadjusted OR	2.73 (1.68-4.43)	0.63 (0.22-1.79)	0.01
	Potassium <3.5 mmol/L
	Events, n (%)	263 (13.8)	130 (7.0)	36 (11.8)	24 (7.5)
	Unadjusted OR	0.47 (0.38-0.58)	0.60 (0.35-1.04)	0.41
	Study drug discontinuation (all-cause)
	Events, n (%)	377 (19.8)	365 (19.6)	64 (21.1)	7 1 (22.1)
	Unadjusted OR	0.99 (0.84-1.16)	1.08 (0.73-1.58)	0.73

COPD, chronic obstructive pulmonary disease; MRA, mineralocorticoid receptor antagonist; OR, odds ratio with 95% confidence interval.

© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Funding

This work was supported by the British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217.

Supplementary Information

Additional supporting information may be found online in the Supporting Information section at the end of the article. Conflict of interest: J.J.V.M. employer has been paid by Cardiorentis, Amgen, Oxford University/Bayer, Abbvie, Bristol-Myers Squibb, Kings College Hospital/Kidney Research UK/Vifor-Fresenius, Theracos, Pfizer, Merck, Novartis, Bayer, DalCor Pharmaceuticals, GlaxoSmithKline. All payments for meetings-related travel and accommodation were made through a Consultancy with the University of Glasgow, and J.J.V.M. has not received personal payments in relation to any trials or drugs. B.P. reports personal fees (consulting) from Bayer, KBP Pharmaceuticals, AstraZeneca, Relypsa/Vifor, Sanofi, sc Pharmaceuticals, Sarfez pharmaceuticals, Stealth Peptides, Cereno Scientific, SQinnovations, G3 pharmaceuticals, Ardelyx and Tricida; stock options from KBP Pharmaceuticals, sc Pharmaceuticals, Sarfez pharmaceuticals, Relypsa, Cereno scientific, SQinnovations, G3 pharmaceuticals, Ardelyx and Tricida; patent for site specific delivery of eplerenone to the myocardium US patent Number 9931412. F.Z. reports personal fees for Steering Committee membership from Janssen, Bayer, Pfizer, Novartis, Boston Scientific, Resmed, Takeda, General Electric, and Boehringer Ingelheim; consultancy for Amgen, CVRx, Quantum Genomics, Relypsa, ZS Pharma, AstraZeneca, GSK; founder of Cardiovascular Clinical Trialists (CVCT) and of CardioRenal. Profs McMurray, Pitt, Swedberg, van Veldhuisen, and Zannad received remuneration from Pfizer as members of the EMPHASIS-HF Executive Steering Committee. P.S.J. has received consulting, advisory board, and speaker's fees from Novartis, advisory board fees from Cytokinetics, and a grant from Boehringer Ingelheim. J.P.F. has received consulting fees from Boehringer Ingelheim. All other authors have nothing to disclose.