A prospective,randomized study to evaluate the efficacy of various diuretic strategies in acute decompensated heart failure

Aim

To evaluate the safety and efficacy of various initial strategies of loop diuretic administration in patients with acute decompensated heart failure (ADHF) on diuresis, renal function, electrolyte balance and clinical outcomes.

Methods

Consecutive patients admitted with ADHF were randomized into three groups - intravenous furosemide infusion + intravenous dopamine, intravenous furosemide bolus in two divided doses and intravenous furosemide continuous infusion alone. At 48 h, the treating physician could adjust the diuretic strategy. Primary endpoint was negative fluid balance at 24 h after admission. Secondary end points were duration of hospital stay, negative fluid balance at 48, 72, 96 h, the trend of serum electrolytes, and renal function and 30 day clinical outcome (death and emergency department visits).

Results

Overall ninety patients (thirty in each group) were included in the study. There was a greater diuresis in first 24 h (p = 0.002) and a shorter hospital stay (p = 0.023) with the bolus group. There was no significant difference in renal function and serum sodium and serum potassium levels. There was no difference in the number of emergency department visits among the three groups.

Conclusion

All three modes of diuretic therapies can be practiced with no difference in worsening of renal function and electrolyte levels. Bolus dose administration with its rapid volume loss and shorter hospital stay might be a more effective diuretic strategy.     

Fractional excretion of sodium predicts worsening renal function in acute decompensated heart failure

BACKGROUND:

Renal impairment (RI), defined as an increase in creatinine level of greater than 26.5 mmol/L, develops in more than 30% of acute decompensated heart failure (ADHF) patients. Fractional excretion of sodium (FeNa) reflects sodium handling by the kidneys during diuresis.

AIM:

To study the relationship between FeNa and RI in patients admitted with ADHF.

METHOD:

The hospital course and renal function of all ADHF patients admitted to the hospital were prospectively observed. Patients were included if their admission creatinine level was 176 mmol/L or lower, they had been on a low-salt diet since admission, had urine sodium and creatinine samples collected more than 6 h after a furosemide dose in the first few days of admission, and they were on daily intravenous furosemide doses of 20 mg or more.

RESULTS:

Over six months, 51 patients met the inclusion criteria; the average daily dose of intravenous furosemide was 58.8 mg. RI developed in 39% of patients. A FeNa cut-off point of 0.4% was determined using ROC curve analysis; patients with a FeNa of greater than 0.4% (28 patients) were compared with patients with a lower FeNa (23 patients). Admission creatinine level and furosemide dose were higher in the first group (P=0.01 and P=0.06, respectively). The first group developed RI more frequently (OR=6.3; 95% CI 1.7 to 23.5; P=0.0047; adjusted OR for admission creatinine = 6.18; 95% CI 1.6 to 24.5; P=0.0096; and adjusted OR for furosemide dose = 4.7; 95% CI 1.3 to 16.7; P=0.016). They had a longer hospitalization course (median nine days [interquartile range 6.3 to 13.5 days] versus seven days [interquartile range 4.0 to 9.0 days]; P=0.036) and they were admitted to the cardiac care unit more frequently (OR=6.8; 95% CI 1.3 to 34.9; P=0.02).

CONCLUSION:

A FeNa of greater than 0.4% more than 6 h after a dose of diuretics predicts RI and a complicated hospital course in ADHF patients.     

Loop diuretic use among patients with heart failure and type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors

AimsTo compare loop diuretic use in patients with comorbid heart failure (HF) and type 2 diabetes (T2D) newly initiated on sodium glucose cotransporter-2 inhibitors (SGLT2Is) versus other oral anti-glycemic agents (AGAs).MethodsThis analysis used 2013–2015 MarketScan Medicare Supplemental claims data. HF and T2D patients were identified and SGLT2I users were propensity score matched to other AGA users. The mean daily dose of loop diuretics in furosemide equivalents was ascertained. For those not on baseline loop diuretics, new use was compared between cohorts. For those on baseline loop diuretics, we assessed patterns of use (increased dose, decreased dose, stable dose, no longer using) at 12-months.ResultsA total of 750 SGLT2I users were matched to 750 other AGA users. The distribution of loop diuretic use at mean doses of 0 mg (i.e., no use), ≤20 mg, >20 mg–40 mg, >40 mg–80 mg and >80 mg/day did not differ between cohorts at baseline or 12-months (p > 0.05 for both). SGLT2I use was associated with less new loop diuretic use (22.7% [79/348] vs. 34.0% [132/388]; p = 0.001). For those on loop diuretics at baseline (n = 764), patterns of use at 12-months did not differ between cohorts (p = 0.14).ConclusionsNew loop diuretic use was less frequent among SGLT2I users; however, patterns of loop diuretic use did not differ between cohorts in those on loop diuretics at baseline.     

Continuous infusion of furosemide in the treatment of patients with congestive heart failure and diuretic resistance

Objectives . To assess the value of treatment with continuous intravenous infusion of furosemide (F) in patients with refractory congestive heart failure. Design . Open uncontrolled dose-response study. Subjects . Patients with congestive heart failure (those with New York Heart Association (NYHA) classes III and IV with an assessed amount of oedema of more than 5 kg and diuretic resistance were included [n = 10]). Diuretic resistance was defined as: failure to lose weight and/or inappropriate urinary sodium excretion (50 mmol 24 h^-1) despite bed rest for a period of 2–3 days, salt and water restriction, orally and intravenously administered furosemide in a dose of 250 mg day^-1, digoxin, and when possible an ACE inhibitor. Included patients were treated with continuous F infusion at a delivery rate of 20 mg^-1 over 24 h. The infusion rate was gradually heightened up to a maximum dose of 160 mg h^-1. Main outcome measures . Daily physical examination, history of side-effects, determination of serum electrolytes and 24-h electrolyte excretion during treatment with furosemide. Results . Weight loss (mean ± sd ; 12.5 ± 5 kg) and relief of symptoms was achieved in all patients. Mean (± sd ) 24-h sodium output rose from 19 ± 16 mmol 24 h^-1 (n = 10) on oral therapy with 250 mg F to 137 ± 85 mmol 24 h^-1 (n = 8) during 80 mg h^-1 and to 268 ± 124 mmol 24 h^-1 (n = 3) on the maximal dose of 160 mg h^-1. Conclusion . Continuous infusion of F under careful monitoring of the patient is a safe, controllable and efficient treatment in patients with severe congestive heart failure and diuretic resistance.     

Effect of timed semirecumbency and furosemide dosing on urinary sodium excretion in patients with compensated heart failure

PURPOSE: The management of chronic cardiac failure, a salt-sensitive state, frequently includes administration of a loop diuretic to enhance urinary Na excretion. We hypothesized that a period of timed semirecumbency (vis-à-vis upright posture) would enhance the natriuresis that accompanies oral furosemide dosing in patients with compensated cardiac failure. METHODS: Four ambulatory patients with compensated chronic cardiac failure (NYHA Class III) of ischemic and nonischemic origin and systolic dysfunction (ejection fraction <35%), who were receiving a stable regimen of oral furosemide and angiotensin-converting enzyme inhibitor, were enrolled into the study. In the institution's Clinical Research Center, we monitored and compared urine flow rate (mL/min) and Na excretion rate (mEq/hr) in each patient in response to two different protocols. Protocol 1 consisted of an initial 90-minute period of bedrest followed by the patient's oral furosemide dose and 180 minutes of upright activity and a subsequent 90-minute period of bedrest. Protocol 2 was similar, with the exception that furosemide dosing was given after upright activity and immediately prior to the second period of bedrest. RESULTS: With each patient serving as his or her own control, both urine flow rate and urinary Na excretion rate were markedly increased when furosemide was given prior to bedrest as compared to its dosing prior to upright activity. CONCLUSIONS: In patients with compensated chronic cardiac failure, the natriuresis that accompanies oral furosemide dosing is enhanced when given just prior to a period of timed semirecumbency. This approach represents a more optimal use of this loop diuretic in patients with compensated heart failure.     

The prognostic implications of outpatient diuretic dose in heart failure

In 111 patients with left ventricular ejection fraction < or =30% who required hospitalization for heart failure, we examined the association between outpatient dose of diuretic agents and all-cause mortality. In comparison to patients who were not on treatment with diuretics prior to hospitalization, patients being treated with 'low' doses of diuretics (<80 mg/day of furosemide) and those being treated with 'high' doses of diuretics (> or =80 mg/day of furosemide) were more likely to die during follow-up after adjustment for other clinical parameters (adjusted relative risks, RR, 3.1 and 4.6).     

Empagliflozin in heart failure with preserved ejection fraction with and without atrial fibrillation

Aims

Atrial fibrillation/flutter (AF) is common in heart failure (HF) with preserved left ventricular ejection fraction (LVEF) and associated with worse outcomes. Empagliflozin reduces cardiovascular death or HF hospitalizations and slows estimated glomerular filtration rate (eGFR) decline in patients with HF and LVEF >40%. We aimed to assess the efficacy and safety of empagliflozin in improving outcomes in patients with HF and LVEF >40% with and without AF.

Methods and results

In this pre-defined secondary analysis of EMPEROR-Preserved, we compared the effects of empagliflozin versus placebo on the primary and secondary endpoints and safety outcomes, stratified by baseline AF, defined as AF reported in any electrocardiogram before empagliflozin initiation or in medical history. Among 5988 patients randomized, 3135 (52%) had baseline AF; these patients were older, with worse functional class, more previous HF hospitalizations and higher natriuretic peptides compared to those without AF (all p < 0.001). After a median of 26 months, empagliflozin reduced cardiovascular death or HF hospitalization compared to placebo to a similar extent in patients with and without AF (hazard ratio [HR] 0.78 [95% confidence interval 0.66–0.93] vs. 0.78 [0.64–0.95], interaction p = 0.96). Empagliflozin also reduced total HF hospitalizations (HR 0.73 [0.57–0.94] vs. 0.72 [0.54–0.95], interaction p = 0.94) and annual eGFR decline (difference = 1.368 vs. 1.372 ml/min/1.73 m²/year, interaction p = 0.99) consistently in patients with and without AF. There was no increase in serious adverse events with empagliflozin versus placebo in patients with and without AF.

Conclusions

In patients with HF and ejection fraction >40%, empagliflozin reduced the risk of serious HF events and slowed the eGFR decline regardless of baseline AF.     

Cortical gray matter loss in treatment-naïve alcohol dependent individuals

Background: Most studies of the impact of alcohol dependence on the brain have examined individuals in treatment. Such samples represent a small proportion of alcoholics in the general population. Such samples may embody a bias (Berkson's fallacy) if the association between variables (for example, alcoholism and cortical gray matter loss) differs between the population of alcoholics in treatment and alcoholics in the general population. Our objective was to determine if treatment‐naïve alcoholics show structural brain changes versus controls and to compare our findings with reports evaluating alcoholic samples drawn from treatment populations. Methods: Structural MRI was used to assess whole brain and regional volumes of cortical gray matter and white matter in 24 young to middle‐aged treatment‐naïve alcohol‐dependent males versus 17 controls. Results: Cortical gray matter volumes in alcohol‐dependent individuals were negatively associated with age and lifetime duration of alcohol use (which were highly confounded). These subjects showed reduced whole brain (p < 0.05), prefrontal (p < 0.01), and parietal (p < 0.05) cortical gray matter compared with controls. White matter and temporal cortex, tissues that usually show volume reductions in samples drawn from treatment, did not differ between treatment‐naïve alcoholics and controls (all p > 0.40). Conclusions: Our findings are consistent with the hypothesis that structural brain changes in treatment‐naïve alcoholics are less severe than those reported in clinical samples of alcoholics, perhaps due to less concomitant psychopathology and a reduced severity of alcoholism in treatment‐naïve alcoholics. However, caution must be taken when comparing our findings with results from clinical samples, as we did not directly compare treatment‐naïve alcoholics with treated alcoholics and our treatment‐naïve sample tended to be younger than the (clinical) samples reported in the literature. Nevertheless, we suggest that most of the reports of the central nervous system consequences of alcoholism may not accurately describe the majority of alcoholic‐dependent individuals.     

Definitions of antiretroviral treatment failure for measuring quality outcomes

Objectives

Our aim was to compare three different definitions of treatment failure and discuss their use as quality outcome measures for a clinical service.

Methods

Data for treatment‐naïve patients who attended the Melbourne Sexual Health Centre (MSHC) between 1 January 2000 and 31 December 2008 were analysed. Definition 1 was the strict Food and Drug Administration (FDA) definition of treatment failure as determined using the time to loss of virological response (TLOVR) algorithm. Definition 2 defined treatment failure as occurring in those whose viral load never fell to <400 HIV‐1 RNA copies/mL or who developed two consecutive viral loads ≥400 copies/mL on any treatment (switching or stopping treatment with a viral load <400 copies/mL was permitted). Definition 3 was the same as definition 2 except that individuals were also deemed to have failed if they stopped treatment for 6 months or longer.

Results

There were 310 antiretroviral‐naïve patients who started treatment in the study period. Of these, 156 [50.3%; 95% confidence interval (CI) 42.1–53.3%] experienced treatment failure under definition 1, 10 (3.2%; 95% CI 1.5–5.8%) experienced treatment failure under definition 2, and 16 (4.5%; 95% CI 2.5–7.4%) experienced treatment failure under definition 3 over the 108 months of follow‐up. The probability of failing definition 1 was statistically different from the probability of failing definition 2 or 3 (P=0.01).

Conclusion

There were significant differences in treatment failure for the three definitions. If definition 1 were used, the outcomes would be sufficiently common to enable clinics to be compared but would be less meaningful. If definition 2 or 3 were used, the events would be too rare to enable clinics to be compared, but it would be possible to set a benchmark level of success that clinics could aim to reach.     

Use of piretanide, a new loop diuretic, in cirrhosis with ascites: relationship between the diuretic response and the plasma aldosterone level.

Twenty patients with cirrhosis and ascites but no renal failure were given piretanide, a new loop diuretic, in order to investigate its efficacy and to relate the diuretic response with the pretreatment plasma aldosterone concentration. Eleven patients responded to piretanide 12 mg/day (equivalent in potency to 80 mg furosemide); there was no response in nine patients. Both groups were similar with regard to liver function, plasma urea, serum creatinine, plasma electrolytes, urine volume, and urine potassium concentration. The basal urinary sodium excretion was significantly higher in those patients who responded (23.6 +/- 5.7 mmol/day vs. 4.3 +/- 1.42 mmol/day; P < 0.01) (M +/- SE). Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were normal or only slightly increased in patients who responded to piretanide (PRA = 1.22 +/- 0.20 ng/ml/h; PAC = 12.25 +/- 2.20 ng/100 ml) and very high in patients who did not respond (PRA = 8.71 +/- 1.18 ng/ml/h; PAC = 84.6 +/- 16.2 ng/100 ml) (P < 0.001). Patients unresponsive to piretanide 12 mg/day also failed to respond when the dose was increased to 24 mg/day. However, the addition of spironolactone, 150 mg/day, to piretanide was followed in these patients by a marked increase in diuresis and natriuresis. These results strongly suggest that the pre-treatment level of aldosterone is an important factor influencing the response to loop diuretics in patients with non-azotaemic cirrhosis and ascites.     

Children with severe acute asthma admitted to Dutch PICUs: A changing landscape

The number of children requiring pediatric intensive care unit (PICU) admission for severe acute asthma (SAA) around the world has increased.

Objectives

We investigated whether this trend in SAA PICU admissions is present in the Netherlands.

Methods

A multicenter retrospective cohort study across all tertiary care PICUs in the Netherlands. Inclusion criteria were children (2‐18 years) hospitalized for SAA between 2003 and 2013. Data included demographic data, asthma diagnosis, treatment, and mortality.

Results

In the 11‐year study period 590 children (660 admissions) were admitted to a PICU with a threefold increase in the number of admissions per year over time. The severity of SAA seemed unchanged, based on the first blood gas, length of stay and mortality rate (0.6%). More children received highflow nasal cannula (P < 0.001) and fewer children needed invasive ventilation (P < 0.001). In 58% of the patients the maximal intravenous (IV) salbutamol infusion rate during PICU admission was 1 mcg/kg/min. However, the number of patients treated with IV salbutamol in the referring hospitals increased significantly over time (P = 0.005). The proportion of steroid‐naïve patients increased from 35% to 54% (P = 0.004), with a significant increase in both age groups (2‐4 years [P = 0.026] and 5‐17 years [P = 0.036]).

Conclusions

The number of children requiring PICU admission for SAA in the Netherlands has increased. We speculate that this threefold increase is explained by an increasing number of steroid‐naïve children, in conjunction with a lowered threshold for PICU admission, possibly caused by earlier use of salbutamol IV in the referring hospitals.

     

Furosemide-induced natriuresis is augmented by ultra-low-dose captopril but not by standard doses of captopril in chronic heart failure.

BACKGROUND. Ten chronic heart failure patients were studied on three occasions in randomized double-blind fashion to compare the acute hemodynamic, neurohormonal, and renal sodium-handling responses to 1 mg captopril versus 25 mg captopril, both in the absence of loop diuretic therapy and during furosemide-stimulated natriuresis. METHODS AND RESULTS. Compared with placebo, 1 mg captopril caused nonsignificant decreases in mean arterial pressure and circulating angiotensin II level and had no effect on glomerular filtration rate as determined by 51Cr-EDTA elimination. Captopril (25 mg) produced marked suppression of serum angiotensin II with or without oral furosemide (both p less than 0.002), a marked decrease in mean arterial pressure (p less than 0.001) that was accentuated by furosemide (p less than 0.00001), and a decrease in glomerular filtration rate (p = 0.0007). No difference from placebo in renal sodium excretion was noted with either 1 or 25 mg captopril in the absence of furosemide. In contrast, while 25 mg captopril caused slight attenuation of the natriuretic response to furosemide, 1 mg captopril significantly enhanced furosemide-induced natriuresis (p less than 0.05). No correlation was found in our patients between the natriuretic effect of furosemide and either absolute mean arterial pressure or change in mean arterial pressure during the furosemide phase of each study session. This suggests that blood pressure is not the important factor mediating the divergent renal responses to furosemide of the two captopril dosage regimens. CONCLUSIONS. We propose that in the face of furosemide-induced postglomerular vasodilatation in chronic heart failure, captopril at a starting dose of 1 mg (but not 25 mg) preserves enough circulating angiotensin II to maintain efferent arteriolar tone and thus glomerular filtration, while offsetting the antinatriuretic renal tubular effects of angiotensin II.     

Renal and blood pressure effects of dapagliflozin in recently hospitalized patients with heart failure with mildly reduced or preserved ejection fraction: Insights from the DELIVER trial

Aims

Patients recently hospitalized for heart failure (HF) often have unstable haemodynamics and experience worsening renal failure, and are at elevated risk for recurrent HF events. In DELIVER, dapagliflozin reduced HF events or cardiovascular death including among patients who were hospitalized or recently hospitalized.

Methods and results

We examined the effects of dapagliflozin versus placebo on estimated glomerular filtration rate (eGFR) slope (acute and chronic), 1-month change in systolic blood pressure, and the occurrence of serious hypovolaemic or renal adverse events in patients with and without HF hospitalization within 30 days of randomization. The 654 (90 randomized during hospitalization, 147 1–7 days post-discharge and 417 8–30 days post-discharge) recently hospitalized patients had lower baseline eGFR compared with those without recent HF hospitalization (median [interquartile range] 55 [43, 71] vs. 60 [47, 75] ml/min/1.73 m²). Dapagliflozin consistently reduced the risk of all-cause (p_interaction = 0.20), cardiac-related (p_interaction = 0.75), and HF-specific (p_interaction = 0.90) hospitalizations, irrespective of recent HF hospitalization. In those recently hospitalized, acute placebo-corrected eGFR reductions with dapagliflozin were modest and similar to patients without recent hospitalization (−2.0 [−4.1, +0.1] vs. −3.4 [−3.9, −2.9] ml/min/1.73 m², p_interaction = 0.12). Dapagliflozin's effect to slow chronic eGFR decline was similar regardless of recent hospitalization (p_interaction = 0.57). Dapagliflozin had a minimal effect on 1-month systolic blood pressure and to a similar degree in patients with and without recent hospitalization (−1.3 vs.−1.8 mmHg, p_interaction = 0.64). There was no treatment-related excess in renal or hypovolaemic serious adverse events, irrespective of recent HF hospitalization.

Conclusion

In patients recently hospitalized with HF, initiation of dapagliflozin had minimal effects on blood pressure and did not increase renal or hypovolaemic serious adverse events, yet afforded long-term cardiovascular and kidney protective effects. These data suggest that the benefit to risk ratio favours initiation of dapagliflozin among stabilized patients hospitalized or recently hospitalized for HF. Clinical Trial Registration: ClinicalTrials.gov NCT03619213.     

Spot Urine Sodium as Triage for Effective Diuretic Infusion in an Ambulatory Heart Failure Unit

Background

Admission for diuresis remains a common and costly event in patients with advanced heart failure (HF). We tested whether spot urine sodium could identify patients likely to respond to ambulatory diuretic infusion without hospitalization.

Association of serum uric acid change with mortality,renal function and diuretic dose administered in treatment of acute heart failure

Background and aims

Hyperuricemia is reportedly associated with poor outcome in acute heart failure (AHF). The association between changes in Uric acid (UA) levels with renal function change, diuretic doses, and mortality in patients with AHF were studied.

A 2018 overview of diuretic resistance in heart failure

Heart failure is a disease with high direct and indirect costs. Current treatment includes drugs that alter disease progression and drugs that to improve symptoms. Loop diuretics are the cornerstone of congestion relief for acute management, as well as for chronic stabilization. In heart failure patients, maximal diuretic response is reduced by many individual factors. Diuretic resistance is defined as failure to achieve effective congestion relief despite appropriate or escalating diuretic doses. Its causes include impaired delivery of the diuretic to its luminal site of action, neurohormonal activation, tubular compensatory adaptation and drug interactions. Several strategies can be employed to aid decongestion of patients with impaired diuretic response. These include salt restriction, a higher effective single dose or higher dose frequency of loop diuretics, continuous infusion of diuretics and/or sequential nephron blockade through a synergistic combination of two or more diuretics from different classes. Ultrafiltration has also been found to be another effective and safe therapeutic option and should be considered in patients with refractory diuretic resistance. Overall, there is a lack of high-quality clinical data to guide the choice of treatment strategy and therapy should be tailored on a case-by-case basis.     

Aspirin inhibits the acute venodilator response to furosemide in patients with chronic heart failure

OBJECTIVES: We sought to determine the effect of aspirin on the venodilator effect of furosemide in patients with chronic heart failure (CHF) BACKGROUND: Furosemide has an acute venodilator effect preceding its diuretic action, which is blocked by nonsteroidal anti-inflammatory, drugs. The ability of therapeutic doses of aspirin to block this effect of furosemide in patients with CHF has not been studied. For comparison, the venodilator response to nitroglycerin (NTG) was also studied. METHODS: Eleven patients with CHF were randomized to receive placebo, aspirin at 75 mg/day or aspirin at 300 mg/day for 14 days in a double-blind, crossover study. The effect of these pretreatments on the change in forearm venous capacitance (FVC) after 20 mg of intravenous furosemide was measured over 20 min by using venous occlusion plethysmography. In a second study, the effect of 400 microg of sublingual NTG on FVC was documented in 11 similar patients (nine participated in the first study). RESULTS: Mean arterial pressure, heart rate and forearm blood flow did not change in response to furosemide. After placebo pretreatment, furosemide caused an increase in FVC of 2.2% (95% confidence interval [CI] -0.9% to 5.2%; mean response over 20 min). By comparison, FVC fell by -1.1% (95% CI -4.2% to 1.9%) after pretreatment with aspirin at 75 mg/day, and by -3.7% (95% CI -6.8% to -0.7%) after aspirin at 300 mg/day (p = 0.020). In the second study, NTG increased FVC by 2.1% (95% CI -1.6% to 5.8%) (p = 0.95 vs. furosemide). CONCLUSIONS: In patients with CHF, venodilation occurs within minutes of the administration of intravenous dose of furosemide. Our observation that aspirin inhibits this effect further questions the use of aspirin in patients with CHF.     

Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: Insights from the EMPEROR-Preserved trial

Aim

In the EMPEROR-Preserved trial, empagliflozin improved clinical outcomes of patients with heart failure (HF) with preserved ejection fraction. In this pre-specified analysis, we aim to study the effect of empagliflozin on cardiovascular and kidney outcomes across the spectrum of kidney function.

Methods and results

Patients were categorized by the presence or absence of chronic kidney disease (CKD) at baseline (CKD defined by an estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m² or urine albumin to creatinine ratio >300 mg/g). The primary and key secondary outcomes were (i) a composite of cardiovascular death or first HF hospitalization (primary outcome); (ii) total number of HF hospitalization, (iii) eGFR slope; and a pre-specified exploratory composite kidney outcome including a sustained ≥40% decline in eGFR, chronic dialysis or renal transplant. The median follow-up was 26.2 months. A total of 5988 patients were randomized to empagliflozin or placebo, of whom 3198 (53.5%) had CKD. Irrespective of CKD status, empagliflozin reduced the primary outcome (with CKD: hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.69–0.94; without CKD: HR 0.75, 95% CI 0.60–0.95; interaction p = 0.67) and total (first and recurrent) hospitalizations for HF (with CKD: HR 0.68, 95% CI 0.54–0.86; without CKD: HR 0.89, 95% CI 0.66–1.21; interaction p = 0.17). Empagliflozin slowed the slope of eGFR decline by 1.43 (1.01–1.85) ml/min/1.73 m²/year in patients with CKD and 1.31 (0.88–1.74) ml/min/1.73 m²/year in patients without CKD (interaction p = 0.70). Empagliflozin did not reduce the pre-specified kidney outcome in patients with or without CKD (with CKD: HR 0.97, 95% CI 0.71–1.34; without CKD: HR 0.92, 95% CI 0.58–1.48; interaction p = 0.86) but slowed progression to macroalbuminuria and reduced the risk of acute kidney injury. The effect of empagliflozin on the primary composite outcome and the key secondary outcomes was consistent across five baseline eGFR categories (all interaction p >0.05). Empagliflozin was well tolerated independent of CKD status.

Conclusions

In EMPEROR-Preserved, empagliflozin had a beneficial effect on the key efficacy outcomes in patients with and without CKD. Overall, the benefit and safety of empagliflozin was consistent across a wide range of kidney function spectrum, down to a baseline eGFR of 20 ml/min/1.73 m².