Eligibility for dapagliflozin in unselected patients hospitalised with decompensated heart failure

Patients with heart failure with reduced ejection fraction (HFrEF) who received the sodium-glucose co-transport 2 inhibitor, dapagliflozin, in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) study have a significant reduction in worsening heart failure (HF) and cardiovascular death. It is uncertain what proportion of patients admitted to a large regional cardiac centre with decompensated heart failure would be eligible for dapagliflozin post-discharge based on their characteristics at discharge.

The DAPA-HF study criteria were retrospectively applied to a cohort of 521 consecutive patients referred to the inpatient HF service in a tertiary cardiac centre in South West Wales between April 2017 and April 2018. Inclusion criteria: left ventricular ejection fraction (LVEF) <40%, New York Heart Association (NYHA) class II–IV symptoms and an elevated N-terminal pro-B-type naturietic peptide (NT-proBNP). Exclusion criteria: systolic blood pressure (SBP) <95 mmHg, estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m² or type 1 diabetes mellitus. We did not have complete NT-proBNP data for the cohort, as it was not routinely measured at the time in our institute.

There were 478 patients, mean age 78 ± 13 years, 57% male and 91% NYHA class II–IV symptoms, were included in the analysis. Of these, 247 patients had HFrEF, 219 (46%) patients met the inclusion criteria, 231 (48%) were excluded as LVEF was >40%, and 48 (10%) were excluded with NYHA class I symptoms. Of the 219 patients who met the inclusion criteria, 13 (5.9%) had a SBP <95 mmHg, 48 (22%) had eGFR <30 ml/min/1.73 m², leaving 136 (28.5% of total and 55% of those with HFrEF) who met DAPA-HF study criteria.

In our study, 28.5% of all heart failure admissions and 55% of patients with HFrEF would be eligible for dapagliflozin post-discharge according to the DAPA–HF study entry criteria.

Introduction

Diabetes is a major risk factor for developing cardiovascular disease. It is common in patients with heart failure (HF), associated with poorer functional status and worsens prognosis.^1-3 The management of diabetes has, until recently, been focused on the lowering of glucose and glycosylated haemoglobin (HbA_1c). However, not all HbA_1c-lowering treatments have beneficial effects on cardiovascular outcomes.1 In fact, intensive glucose or HbA_1c lowering with specific drugs may be associated with adverse cardiovascular outcomes.⁴ Sodium-glucose co-transport 2 (SGLT2) inhibitors, which inhibit the glucose reabsorption in the proximal renal tubule, and reduce hyperglycaemia, HbA_1c levels, body weight and blood pressure in patients with type 2 diabetes mellitus (T2DM), may be a major step forward.^5,6 In randomised-controlled trials, involving patients with T2DM at high risk for cardiovascular events, SGLT2 inhibitors have been shown to reduce cardiovascular death and hospitalisation for HF.^7-9

In the past 30 years, several trials on neurohormonal antagonists – angiotensin-converting enzyme inhibitors (ACEi),^10,11 angiotensin-receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs),^12,13 angiotensin receptor–neprilysin inhibitor (ARNI),¹⁴ and beta blockers^15,16 – have shown a significant benefit in improving symptoms, and prognosis, and reducing hospitalisation in patients with HFrEF. In the Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction (DAPA-HF) study, patients with HFrEF who received dapagliflozin on top of standard HF treatment had a significant reduction in the primary outcome of combined worsening HF and death from cardiovascular causes compared with placebo, regardless of the presence or absence of diabetes (hazard ratio 0.74; 95% confidence interval [CI] 0.65 to 0.85; p<0.001).¹⁷

In the DAPA-HF study, patients were excluded if they had been admitted to hospital with decompensated heart failure in the previous four weeks. The point of discharge, however, is an opportune time to review prognostic HF therapies for patients with HF and plan treatment for the coming weeks. We, therefore, took the point of discharge as the practical clinical reference point for our study to make recommendations for post-discharge use of dapagliflozin. It is uncertain what proportion of patients with HFrEF admitted to a tertiary cardiac centre with HF would be eligible for dapagliflozin post-discharge.

Method

In this retrospective study, we initially applied the DAPA-HF study inclusion and exclusion criteria, other than the exclusion criterion of being within four weeks of acute decompensation for the practical reasons described above.¹⁷ Subsequently, we applied the European Medicines Agency (EMA) pre-October 2020 licence criteria for dapagliflozin (table 1). These two criteria were applied to consecutive inpatients admitted with decompensated heart failure to assess the eligibility for dapagliflozin post-discharge.

Patients admitted to the tertiary centre with decompensated HF and referred to the inpatient HF team at a regional cardiac centre in Morriston Hospital, Swansea, UK, from April 2017 to April 2018 were included.

Clinical notes and electronic records of 521 patients who were referred to the HF team were reviewed retrospectively by HK, PS and SB. Demographics, symptoms and signs, haematology and biochemistry profiles, electrocardiographs (ECGs), and echocardiograms were systematically recorded to assess eligibility according to the two criteria. The inclusion criteria required to be eligible for the DAPA-HF study, included: age over 18 years, left ventricular ejection fraction (LVEF) <40%, New York Heart Association (NYHA) class II or more symptoms and an elevated N-terminal pro-B-type naturietic peptide (NT-proBNP) (table 1).¹⁷ Patients received standard medical or device treatment for their HF and diabetes according to published guidelines.

The LVEF was assessed visually using echocardiography by a trained cardiac physiologist during the admission with HF. Patients with HF were categorised according to their LVEF into one of the following three categories: LVEF >50%, known as heart failure with preserved ejection fraction (HFpEF), LVEF 40–49%, known as heart failure with mid-range ejection fraction (HFmrEF), and LVEF <40%, known as HFrEF. At the time of data collection, NT-proBNP was not routinely measured in patients presenting with HF in our centre. Patients who had a systolic blood pressure (SBP) <95 mmHg, estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m², type 1 diabetes mellitus (T1DM) or allergies to SGLT2 inhibitors were not eligible.¹⁷ Incomplete records for symptoms, investigations or medications were recorded as unknown. The full list of inclusion and exclusion criteria, as applied in the DAPA-HF trial, is listed in table 1.

We initially applied the criteria from the DAPA-HF study, to establish the proportion of patients who would be eligible for a SGLT2 inhibitor, applying the criteria at the point of discharge. We subsequently applied the EMA licence criteria for dapagliflozin for treatment of diabetes to establish which patients with HFrEF would be eligible under the pre-October 2020 diabetes licence (table 1).¹⁸ According to the diabetes licence, dapagliflozin can be initiated in patients with diabetes as a monotherapy (if intolerant to metformin) or in combination with other oral hypoglycaemic agents. Dapagliflozin cannot be initiated in patients with eGFR <60 ml/min/1.73 m² and should be stopped if the eGFR is persistently less than 45 ml/min/1.73 m². T1DM is not an absolute contraindication according to EMA product characteristics. Eligible patients need to undergo an assessment of their risk of diabetic ketoacidosis (DKA). The EMA also stated that patients with fluctuation in insulin due to non-compliance, errors, acute medical illness, surgery, calorie and carbohydrate restriction, chronic underdosing, previous history of DKA, elevated ketones, excessive alcohol and illicit drug use, should not receive dapagliflozin. On 15 October 2020, the EMA revised the licence for dapagliflozin to include the treatment of symptomatic chronic HFrEF. They did not define a precise LVEF eligibility and did not define an eGFR below which dapagliflozin should not be prescribed. However, they commented that there was little experience of the drug in patients with an eGFR <30 ml/min. For the purposes of our study we have used the DAPA-HF entry criteria of LVEF <40% and eGFR >30 ml/min/1.73 m². A full list of the EMA licensing criteria is in table 1.

Statistical analysis

Categorical data are presented as number and percentages; normally distributed, continuous data as mean ± standard deviation (SD); and non-normally distributed continuous variables as median and interquartile range (IQR). All analyses were performed using SPSS (v.25) software.

Results

There were 521 patients referred to the HF team during the study period; 43 (8.3%) were excluded from analysis, 31 (5.9%) died during the admission, 12 (2.3%) did not have a diagnosis of HF and 1 (0.2%) was transferred for a left ventricular assist device (figure 1). The remaining 478 patients had a mean age of 78 ± 13 years, 57% were male, 41% had an ischaemic cause for their HF and 91% were in NYHA class II–IV, and were included in the analysis (table 2). Compared with patients with HFrEF, patients with HFmrEF and HFpEF were older, more commonly female and less likely to have ischaemic heart disease.

There were no patients with T1DM in our study population. Of the 478 patients with HF, 153 (32%) patients had T2DM and the most common antiglycaemic agent was metformin (n=59, 12%) followed by insulin (n=37, 8%). There were no patients on SGLT2 inhibitors. Of HF patients, 56% (n=268) received ACEi, 11% (n=52) ARB, 71% (n=337) beta blocker and 41% (n=198) MRA. Use of an ARNI was only 1% (n=5) in our study population, as it was a relatively novel therapy.

Eligibility for dapagliflozin according to DAPA-HF study

Of 247 patients with HFrEF (LVEF <40%), 219 patients met the inclusion criteria for entry into the DAPA-HF study (NYHA class II–IV). Of these 219 patients, 61 (27.9%) met the exclusion criteria: 13 (5.9%) had a SBP <95 mmHg, 48 (22%) had eGFR <30 ml/min/1.73 m² and 22 (10%) had both SBP <95 mmHg and eGFR <30 ml/min/1.73 m², leaving 136 (28.5% of total and 55% of those with HFrEF) who met DAPA-HF study criteria for dapagliflozin.

Dapagliflozin and EMA licensing prior to 15 October 2020

The EMA licensing for diabetes (table 1), permits use of dapagliflozin in diabetes with eGFR >60 ml/min/1.73 m². The mean eGFR associated with the patients included in our analysis is 51 ± 23 ml/min/1.73 m². Of the 136 patients who met the DAPA-HF study criteria, 70 (51%) would not have been eligible for dapagliflozin in real-world use because of an eGFR ≤60 ml/min/1.73 m², 93 (68%) because they were not diabetic and 23 (17%) patients were not diabetic and had an eGFR ≤60 ml/min/1.73 m². This leaves 14 (3%) patients who met the DAPA-HF study entry criteria based on the pre-October 2020 EMA licensing (table 2 and figure 1).

Discussion

In this real-world retrospective analysis of 521 patients referred to a tertiary inpatient HF service, 55% of the patients with HFrEF would be eligible for dapagliflozin according to the DAPA–HF study entry criteria applied at discharge. This could be an opportune time to consider dapagliflozin in patients with HFrEF.

Recent studies on SGLT2 inhibitors have established them as treatment for diabetes, not only because they improve glycaemic control, but also cardiovascular outcomes, death and HF hospitalisations.^7,9,19 These positive results have prompted the recent DAPA-HF study of patients with established HFrEF, with or without diabetes, and compares dapagliflozin with placebo. Patients on dapagliflozin had a significant reduction in the primary combined outcome of worsening HF (unplanned hospitalisation or urgent visit resulting in intravenous therapy for HF) or cardiovascular mortality (dapagliflozin group 16.3% vs. 21.2% in the placebo group, hazard ratio 0.74, confidence interval 0.59 to 0.83, p<0.001).¹⁷ In the DAPA-HF study there was an early significant divergence of improvement in hospitalisation for HF. This early reduction in the risk of hospitalisation for HF has led to further investigation of the mechanism of action of SGLT2 inhibitors. In addition to diuretic and related haemodynamic actions of SGLT2 inhibitors, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, and vascular function have also been proposed.^20-22 These actions, along with preservation of renal function, would also benefit patients with established HF, including those without diabetes.²³ Even though the mechanism of action is not certain, the improvement in outcomes occurs soon after initiation of SGLT2 inhibitors. It should, therefore, be prudent to initiate dapagliflozin as soon as possible in patients with HFrEF. We have shown that 55% of patients with HFrEF admitted with decompensated HF would be eligible to start dapagliflozin post-discharge based on their characteristics at the time of discharge. The Effects of Empagliflozin on Clinical Outcomes in Patients With Acute Decompensated Heart Failure (EMPA-RESPONSE AHF) study has shown even earlier initiation of empagliflozin may have beneficial effects. In this randomised trial, 80 patients with acute HF, with and without diabetes, received placebo and 10 mg empagliflozin for 30 days. Starting at day one, empagliflozin improved the combined secondary end point (worsening HF, rehospitalisation for HF or death at 60 days; empagliflozin 4 [10%] vs. placebo 13 [33%]; p=0.014), however, there was no difference in visual analogue scale dyspnoea score, diuretic response (weight change per 40 mg furosemide), length of stay, or change in NT-proBNP.

The recent DAPA-HF study results may create a change in the routine management of patients with HF over and above the conventional triple therapy of optimal ACEi/ARB, beta blocker and MRAs. Quadruple therapy in the form of an additional SGLT2 inhibitor should now be considered early in the treatment of patients with HFrEF, regardless of the presence of diabetes. HF hospitalisations account for 70% of healthcare expenditure in HF treatment.²⁴ The DAPA-HF study showed a 30% reduction in the risk of HF hospitalisation, therefore, in a public funded healthcare system like the National Health Service (NHS) in the UK, where dapagliflozin is not a particularly expensive drug, the balance between cost, cost offset, and overall cost-effectiveness is likely to be favourable. The National Institute for Health and Care Excellence (NICE) is currently appraising the clinical and cost-effectiveness of dapagliflozin within its marketing authorisation for treating adults with chronic HFrEF (ID1656).

HF affects 1–2% of the adult population in the western world and the prevalence increases with age, reaching 7–8% in those aged over 75 years.^25-29 Epidemiological studies suggest that roughly half the patients with HF have a reduced LVEF (<40%) while slightly less than half have normal LVEF (LVEF >50%).^30-32 DAPA-HF included only patients with HFrEF and, even though the study criteria included patients with eGFR <30 ml/min/1.73 m², the mean eGFR in the cohort was 66 ml/min/1.73 m². This would exclude a large proportion of patients with HF who have LVEF >40% and/or impaired kidney function. However, in the recent DAPA-CKD study of patients with chronic kidney disease, compared with placebo, dapagliflozin had a lower risk of the primary composite outcome of a sustained decline in the eGFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. These results are reassuring and allow treatment of patients with cardiorenal syndrome. The results from Dapagliflozin in Preserved Ejection Fraction Heart Failure (PRESERVED-HF) and Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER) are eagerly awaited.

Limitations

During the study period, NT-proBNP was not routinely measured when patients were admitted with decompensated HF. There were 31 patients who did not have echocardiography during their admission and had no previous echocardiography, they were, therefore, not considered as eligible for dapagliflozin. There were 95 patients that did not have a heart rate and blood pressure recorded in their discharge summary and, therefore, we had to label them as missing data, as this was a retrospective analysis.

The DAPA-HF study looked at outpatients with chronic HF who were either stable, or at least four weeks post-discharge from an acute decompensation. This four-week point is not particularly practical for assessing such patients admitted to hospital, we, therefore, applied the criteria at discharge. There could, however, be changes in their characteristics between discharge and this four-week point that would change their eligibility for dapagliflozin.

Conclusion

The recent advancements in the pharmacological management of patients with HF offer the potential to further reduce mortality, morbidity and hospitalisations for decompensated HF. This study has demonstrated that almost half of the patients with HFrEF and around a quarter of all patients referred to a tertiary HF service would be eligible for dapagliflozin according to trial inclusion/exclusion criteria. In light of this, the EMA licence for dapagliflozin has recently been updated

Key messages

• In the DAPA-HF (Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction) study, on top of optimal heart failure (HF) management, dapagliflozin showed a significant reduction in worsening HF and cardiovascular death
• The point of discharge after an admission with decompensated HF is an opportune time to review prognostic HF therapies and plan treatment for the coming weeks
• This retrospective study has demonstrated that almost half of the patients with HF and reduced ejection fraction, and around a quarter of all patients referred to a tertiary HF service, would be eligible for dapagliflozin post-discharge
• Sodium-glucose co-transport 2 (SGLT2) inhibitors will now become one of the five pillars of HF treatment, which includes renin–angiotensin system inhibition, beta-blockade, mineralocorticoid receptor antagonists and angiotensin receptor/neprilysin inhibitors

Conflicts of interest

None declared.

Funding

None.

Study approval

This was a retrospective analysis of patients admitted with decompensated heart failure. Patients did not actively participate in the study and did not receive any new investigations or treatment. The study was registered with the local audit and quality improvement department who regulated access to patient records and data. Ethical approval via an ethics committee was not sought in addition to this.

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