Effects of dapagliflozin in heart failure with reduced ejection fraction and chronic obstructive pulmonary disease: an analysis of DAPA‐HF

Aims Chronic obstructive pulmonary disease (COPD) is an important comorbidity in heart failure (HF) with reduced ejection fraction (HFrEF), associated with worse outcomes and often suboptimal treatment because of under‐prescription of beta‐blockers. Consequently, additional effective therapies are especially relevant in patients with COPD. The aim of this study was to examine outcomes related to COPD in a post hoc analysis of the Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure (DAPA‐HF) trial. Methods and results We examined whether the effects of dapagliflozin in DAPA‐HF were modified by COPD status. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. Overall, 585 (12.3%) of the 4744 patients randomized had a history of COPD. Patients with COPD were more likely to be older men with a history of smoking, worse renal function, and higher baseline N‐terminal pro B‐type natriuretic peptide, and less likely to be treated with a beta‐blocker or mineralocorticoid receptor antagonist. The incidence of the primary outcome was higher in patients with COPD than in those without [18.9 (95% confidence interval 16.0–22.2) vs. 13.0 (12.1–14.0) per 100 person‐years; hazard ratio (HR) for COPD vs. no COPD 1.44 (1.21–1.72); P < 0.001]. The effect of dapagliflozin, compared with placebo, on the primary outcome, was consistent in patients with [HR 0.67 (95% confidence interval 0.48–0.93)] and without COPD [0.76 (0.65–0.87); interaction P‐value 0.47]. Conclusions In DAPA‐HF, one in eight patients with HFrEF had concomitant COPD. Participants with COPD had a higher risk of the primary outcome. The benefit of dapagliflozin on all pre‐specified outcomes was consistent in patients with and without COPD. Clinical Trial Registration: ClinicalTrials.gov ID NCT03036124.


Introduction
Chronic obstructive pulmonary disease (COPD) has a higher prevalence in patients with heart failure (HF) than in the general population. [1][2][3] While this most likely reflects the common aetiological role of smoking in each condition, inflammation and oxidative stress have also been postulated to play a role. 1-3 COPD is important in HF for two principal reasons. First, HF patients with COPD have worse outcomes, including higher mortality, than HF patients without COPD. [1][2][3][4][5][6] Second, concomitant COPD has implications for the use of specific HF therapies. [1][2][3]7 Physicians may be reluctant to use beta-blockers in HF patients with COPD, because of their bronchospastic effects, even though these drugs are lifesaving in patients with HF with reduced ejection fraction (HFrEF). Although still indicated and generally well tolerated in most patients with COPD, even in high-risk settings, new evidence also shows that beta-blockers can increase the risk of respiratory hospitalization in patients with more severe COPD. 8,9 It is also advised that hydralazine and isosorbide dinitrate are avoided in patients with COPD as this combination may lead to worsening gas exchange and hypoxaemia. 7 Similarly, hypokalaemia induced by beta-agonists, glucocorticoids and xanthine derivatives may make digoxin use more hazardous in patients with COPD, compared to those without and increase risk of arrhythmias. 7,10,11 Consequently, there is a need for new therapies, both in addition to conventional treatment and, occasionally, as an alternative due to non-tolerance of standard pharmacotherapies, in these high-risk individuals with both HFrEF and COPD. Recently, specific sodium-glucose co-transporter 2 inhibitors have demonstrated reduction in mortality and risk of HF hospitalization in patients with HFrEF. [12][13][14] In this post hoc analysis, we examined the effects of dapagliflozin in HFrEF patients with and without COPD enrolled in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial. 12,15,16 Methods DAPA-HF was a randomized, double-blind, placebo-controlled, event-driven trial in HFrEF patients. 12,15,16 Efficacy and safety of dapagliflozin 10 mg once daily, plus standard care, was compared with matching placebo. The design, baseline characteristics, and primary results are published. 12,15,16 The Ethics Committee of the 410 participating institutions (

Study patients
Enrolment criteria included HF with left ventricular ejection fraction (LVEF) ≤40%, age ≥18 years, New York Heart Association (NYHA) functional class II-IV, elevated N-terminal pro B-type natriuretic peptide (NT-proBNP), and optimal pharmacological and device therapy. The protocol required guideline-recommended medications, including beta-blocker, unless contraindicated/not tolerated. Key exclusion criteria included: symptomatic hypotension/systolic blood pressure <95 mmHg, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m 2 (or rapidly declining renal function), and type 1 diabetes mellitus. No exclusions were related to COPD or asthma.

Identification of chronic obstructive pulmonary disease and study follow-up
An investigator-reported history of COPD was identified from a check box on the case report form. No specific instructions were given in relation to diagnosis of COPD. Investigators reported diagnosis of asthma similarly. There were no respiratory disease or respiratory treatment-related exclusions, although investigators were asked to exclude patients with another condition likely to lead to life expectancy of <2 years. After randomization, follow-up visits occurred at 14, 60, 120, 240, 360 days and every 4 months thereafter.

Study outcomes
The primary trial outcome was the composite of worsening HF (HF hospitalization or urgent visit for HF requiring intravenous therapy) or cardiovascular (CV) death, whichever occurred first. Pre-specified secondary endpoints included HF hospitalization or CV death; HF hospitalizations (first and recurrent) and CV deaths; change from baseline to 8 months in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) 18 ; incidence of worsening renal function and all-cause death (because of few renal events overall, this endpoint was not examined in the present analysis). In addition to the pre-specified outcomes, we also analysed: (i) KCCQ overall summary score (KCCQ-OSS) and KCCQ clinical summary score (KCCQ-CSS), and (ii) non-CV deaths, in view of the potential impact of COPD on quality of life and deaths from respiratory causes and infection. Pre-specified safety analyses included any serious adverse event (AE), AEs related study drug discontinuation, AEs of interest and laboratory findings of note.

Statistical analysis
The primary analysis examined patients with an investigator-reported history of COPD, including a small number with concurrent asthma; patients with asthma alone were examined in supplementary analyses (online supplementary material).
Baseline characteristics were summarized as means (standard deviations), median (interquartile ranges), or percentages. Time-to-event data were evaluated using Kaplan-Meier estimates and Cox proportional-hazards models, stratified by diabetes status, and adjusted for history of HF hospitalization (except for non-CV and all-cause death) and treatment-group assignment. We used a semiparametric proportional-rates model to analyse total (including recurrent) events, as previously described. We also adjusted the effect of COPD status in two additional models: Model 1 included age, sex, region, systolic blood pressure, history of atrial fibrillation, NYHA class III/IV, LVEF, log NT-proBNP, eGFR and smoking status. Model 2 had additional adjustment for baseline beta-blocker and mineralocorticoid receptor antagonist (MRA) prescription. We analysed mean change in KCCQ-TSS from baseline to 8 months. Safety analyses were performed in randomized patients who had received at least one dose of dapagliflozin or placebo (8 of 4744 patients excluded). Interaction between COPD status and treatment effect on the occurrence of the pre-specified safety outcomes was tested in a logistic regression model with an interaction term between baseline COPD status and treatment.
All analyses were conducted using Stata version 16.1 (Stata Corp., College Station, TX, USA). A P-value <0.05 was considered statistically significant.

Results
Overall, 585 (12.3%) of 4744 patients randomized had COPD, 299 (12.6%) in the dapagliflozin group and 286 (12.1%) in the placebo group. Table 1 shows baseline characteristics of those with and without COPD. Patients with COPD were more often male, older and current or ex-smokers, compared to those without COPD. Patients with COPD had lower (worse) median KCCQ-TSS score and a worse NYHA functional class distribution than those without COPD. A similar proportion of patients with and without COPD had a history of coronary heart disease, but patients with COPD had worse renal function, a higher prevalence of atrial fibrillation and higher median NT-proBNP than those without COPD. Patients with COPD were only slightly less likely to be treated with beta-blocker but were also less likely to be prescribed MRA. COPD patients treated with beta-blocker were less likely to be taking a non-selective antagonist and more likely to have been prescribed beta-1 adrenoceptor selective agent than those without COPD.
Baseline characteristics were similar in patients with and without COPD randomized to placebo and dapagliflozin (online supplementary Table S1).
Of the 585 patients with COPD, investigators also reported a diagnosis of asthma in 56 and an additional 133 patients had an investigator-reported diagnosis of asthma only (online supplementary Tables S2 and S3). Patients with asthma only compared to COPD were distinct in several respects, e.g. younger, more likely to be female and much less frequent smoking history. also some similarities between patients with COPD and asthma (as compared to patients without COPD/asthma), including worse KCCQ score, lower eGFR and higher prevalence of atrial fibrillation. Although beta-blocker use was high (91.0%) in patients with asthma only, it was lower than in any other group. Conversely, the use of corticosteroids was highest in patients with asthma, compared with COPD only.
Hospitalization and mortality outcomes in patients with and without chronic obstructive pulmonary disease

Primary outcome
The incidence rate (per 100 person-years) of the primary composite outcome was higher in patients with COPD than in those without [18.9, 95% confidence interval (CI) 16.0-22.2 vs. 13.0, 95% CI 12.1-14.0] ( Table 2, Figure 1, Graphical Abstract and online supplementary Figure S1). Elevated risk persisted after adjustment for other prognostic variables and use of a beta-blocker or MRA. The elevation of risk was somewhat higher when recurrent events were included ( Table 2). Figure 2 shows the excess risk associated with COPD was similar to the risk associated with chronic kidney disease and diabetes, and greater than the other comorbidities examined.

Worsening heart failure events
Adjusted risk of a worsening HF event was also significantly higher in patients with COPD, compared to those without.

Mortality
By contrast, the crude incidence of CV death was only slightly higher in patients with COPD and the adjusted risk was not significantly elevated. However, unadjusted and adjusted risk of death from any cause was higher in patients with COPD, because of a substantially elevated (twofold) risk of non-CV death ( Table 2). The excess of non-CV causes of death in patients with COPD were those attributed to infection and 'other' (online supplementary Figure S2). Mortality and hospitalization rates for patients with asthma only (compared with COPD only) are shown in online supplementary Figure S3. Due to the small number of individuals in the latter group (n = 133), formal statistical testing was not done although the rate of HF hospitalization seemed to be almost as high in patients with COPD (but mortality was similar to patients without COPD or asthma). Figure 3A shows the impact of COPD on self-reported health status. All but one of the KCCQ domains were significantly worse   in patients with COPD, compared to those without. Figure 3B shows health status in patients with COPD, compared with other common comorbidities. Each of the KCCQ scores was lower (worse) in patients with COPD than in participants with other comorbidities. Table 3 and Figure 1 show the effect of dapagliflozin vs. placebo on pre-specified outcomes, according to COPD status.

Worsening heart failure events
The benefit of dapagliflozin, compared with placebo, on worsening HF events was also consistent in patients with and without COPD ( Table 3 and Figure 1).

Mortality
The effects of dapagliflozin on CV (interaction P-value 0.47) and all-cause mortality (interaction P-value 0.96) were also consistent in patients with and without COPD ( Table 3 and Figure 1).

Effect of dapagliflozin on symptoms and quality of life assessed using the Kansas City Cardiomyopathy Questionnaire
In the pre-specified KCCQ analysis, the improvement in KCCQ-TSS with dapagliflozin, compared to placebo, was similar in patients with and without COPD (interaction P-value 0.87) and the same was true for the exploratory analyses of KCCQ-CSS and KCCQ-OSS (Table 3 and Figure 4).

Absolute benefits of dapagliflozin in patients with and without chronic obstructive pulmonary disease
Applying the overall relative risk reduction (26%) to the placebo group event rate in those with COPD gave an absolute risk reduction of 5.9 fewer patients experiencing a primary outcome per 100 person-years. The equivalent reduction in patients without COPD was 3.9 fewer patients per 100 person-years. Applying the overall relative risk reduction (30%) to the placebo group event rate in participants with COPD gave an .

Pre-specified safety assessments
The proportion of patients stopping study drug for any reason in the placebo group was higher in patients with COPD, compared to those without COPD (Table 4). However, the rate of discontinuation was similar between dapagliflozin and placebo in patients with and without COPD (interaction P-value 0.57).
Adverse events related to volume depletion were reported in 7.7% of the placebo group and in 8.4% in the dapagliflozin group in patients with COPD, compared to 6.7% and 7.4%, respectively, in patients without COPD (Table 4 and Graphical Abstract). The rate of renal AEs was numerically (but not significantly) lower in patients treated with dapagliflozin, compared with placebo, both in patients with and without COPD (interaction P-value 0.81).

Figure 2
Risk of primary outcome and all-cause mortality associated with major comorbidities.

Discussion
In DAPA-HF, patients with COPD were older and more commonly men with a history of smoking and atrial fibrillation and had worse renal function and a higher NT-proBNP level, than participants without COPD. Patients with COPD were slightly less likely to be treated with a beta-blocker or MRA and had more severe functional limitation and impairment of quality of life than participants without COPD. During follow-up, patients with COPD experienced higher rates of the primary composite endpoint and key secondary endpoints; fewer had a clinically meaningful improvement (and more deterioration) in symptoms and quality of life, compared to those without COPD. Efficacy and tolerability of dapagliflozin were consistent in participants with and without COPD, with greater absolute risk reductions in hospitalization and death in COPD patients due to their higher overall event rates. Mean improvements in symptoms and quality of life were numerically larger in patients with COPD, compared to those without.
In DAPA-HF, 12.3% of patients had concomitant COPD, very similar to the frequency reported in most other trials, including PARADIGM-HF, where prevalence was 12.9%. [4][5][6][19][20][21] However, this is likely to be lower than the true prevalence of COPD in unselected patients with HFrEF for two reasons. First, the inclusion and exclusion criteria used in trials, including the requirement for patients to be treated with beta-blocker, unless contraindicated or not tolerated, likely led to under-enrolment of patients with severe COPD. Second, use of spirometry would likely have detected undiagnosed COPD. However, the prevalence of COPD in recent registry studies has not been much higher. In the European Society of Cardiology HF Long-Term Registry, the prevalence of COPD was 14.1%. 22 Moreover, 23% of patients in that registry had HF with preserved ejection fraction (HFpEF) and COPD is more common . in HFpEF than HFrEF. 1-3 The proportion of HFrEF patients with COPD in a US registry was 16.5%. 23 In a large Asian registry, prevalence of COPD was 8.3% (but varied across Asia from 4.7% to 11%). 24 As expected, patients with COPD in DAPA-HF had more adverse characteristics including older age and more frequent history of hypertension and, notably, atrial fibrillation. The possibility that beta-agonists increase the risk of atrial fibrillation has been raised previously. 1 Although prior and current smoking were, as expected, more common in patients with COPD, coronary heart disease was not more common. We also found patients with COPD had a higher mean NT-proBNP level, although only modestly so (and this was only the case in patients without atrial fibrillation). There was no clinically relevant difference in LVEF between patients with and without COPD. The latter findings contrasted strikingly with the substantially higher proportion of patients with COPD reported to be in NYHA class III/IV and the significantly lower (worse) KCCQ-TSS (and other KCCQ scores) in people with COPD compared to those without. Indeed, all but one of the domains of KCCQ was worse in patients with COPD compared to most other comorbidities. Although a similar overall mean decrement (−8 points) in KCCQ-OSS was reported in the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training trial (HF-ACTION), we do not know of any other description of the impact of COPD across domains of quality of life/health status or any comparison of the impact of COPD compared to other comorbidities. 5 Interestingly, and in contrast to most prior studies, we found beta-blocker use was high in patients with COPD (92.3%) although not as high as in patients without COPD (96.6%, P < 0.001). This finding may indicate that the recommendation in HF guidelines that COPD is not a contraindication to use of a beta-blocker may have been heeded in this selected clinical trial population. 5,19,20,25,26 More surprisingly, however, was the finding that MRA use was also significantly less common in patients with COPD, despite their worse functional class. A likely explanation is the higher prevalence of renal dysfunction among patients with COPD, compared to those without COPD. 27 . . . . . . . . . . . . . . . . . . . . .
Even after adjusting for differences in demographics, comorbidity, key disease-modifying therapy and NT-proBNP, COPD remained an independent predictor of the primary outcome, although the impact was greater on worsening HF events that on CV death. However, there was a clear association between COPD and death from any cause because of a higher risk of non-CV death in patients with COPD. The excess risk associated with COPD was striking when compared with other common comorbidities, with only chronic kidney disease and diabetes showing a similar hazard; we are not aware of any comparative analysis of this type. These data and our earlier observations on symptoms/quality of life raise two questions about the interaction between COPD and HFrEF. The first is why is COPD associated with worse symptoms and functional status and a higher risk of HF hospitalization? The explanation for the former could simply be that patients experience the extra impact of two cardiac and respiratory conditions causing dyspnoea and effort intolerance (and, potentially, the additional burden of atrial fibrillation). This does not readily explain higher natriuretic peptide levels in patients in sinus rhythm, which may be due to the impact . of COPD on pulmonary artery pressure and right ventricular function. 1,7,28 The benefits of dapagliflozin were consistent in patients with and without COPD, both for worsening HF events and death. This finding is especially important because risk was greater in patients with COPD and, therefore, the absolute risk reduction was larger in these individuals, than in participants without COPD and also because this risk reduction persisted despite the competing (nearly twofold) risk of non-CV death in the COPD group.
Similarly, dapagliflozin was as well tolerated, compared with placebo, in patients with and without COPD. Collectively, this preserved efficacy and tolerability is very important, given the risk faced by patients with COPD and the more limited alternative options for at least some of these patients. 28,29

Limitations
This study has several limitations. The analysis was not pre-specified and the proportion of patients with COPD was relatively small, compared to those without. COPD was investigator-reported, and it is likely that the true prevalence of . . . . . . . . . . . . . . . . .
COPD would probably be higher if all patients had performed spirometry. Participants in this study were selected for a randomized controlled trial and were probably healthier, overall, than 'real-world' patients. Investigators were asked not to include patients with another condition likely to lead to a life-expectancy of <2 years, which may have led to exclusion of patients with severe COPD. The high rate of use of beta-blockers is also consistent with the trial participants representing healthier, better-treated, patients enrolled at sites practicing evidence-based medicine.

Conclusion
In summary, in DAPA-HF, approximately one in eight patients with HFrEF had concomitant COPD. Participants with COPD had worse symptoms and functional limitation, compared to those without, and a higher risk of HF hospitalization and death from any cause. The relative risk reduction with dapagliflozin on all pre-specified mortality/morbidity outcomes was the same in patients with and without COPD (and absolute risk reduction greater in those with COPD because of their higher baseline risk), as was the improvement in symptoms. Dapagliflozin was equally well tolerated, compared with placebo, in patients with and without COPD.