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14th March 2022
Empagliflozin administered to patients once hospitalised with either de novo or decompensated heart failure leads to a clinically significant benefit over the next 90 days. This was the finding of a randomised trial by researchers from the University of Groningen Department of Cardiology, Groningen, The Netherlands.
Among patients with type 2 diabetes, sodium–glucose cotransporter 2 inhibitors such as empagliflozin, have been shown to reduce the risk of hospitalisation for heart failure and the risk of serious adverse renal events. Although an anti-diabetic agent and based on several recent clinical trials, empagliflozin is now also indicated for the treatment of symptomatic chronic heart failure with a reduced ejection fraction.
However, whether the drug would still provide a clinical benefit to patients if given to those already admitted to hospital with heart failure is unknown. For the present study, the Dutch researchers were interested in exploring whether empagliflozin would be clinically advantageous for patients, not only hospitalisation with heart failure but also on reducing worsening heart failure events (HFEs) and on the improvement of symptoms. They performed the Oral EMPagliflozin 10 mg Compared to Placebo, Initiated in Patients Hospitalised for acUte Heart faiLure (de Novo or Decompensated Chronic HF) Who Have Been StabilisEd or EMPULSE trial.
Included patients were those who had a primary diagnosis of acute de novo or decompensated chronic heart failure, irrespective of left ventricular ejection fraction. Individuals were randomised 1:1 to empagliflozin 10 mg or placebo and this occurred after at least 24 hours but no later than 5 days after admission, as early as possible after stabilisation and while still in hospital. The primary outcome of the study was the clinical benefit at 90 days, which was defined as a composite outcome of time to all-cause death, the number of HFEs, the time to the first HFE and a 5- point or greater difference in change from baseline in Kansas City Cardiomyopathy Questionnaire KCCQ after 90 days of treatment. The KCCQ is patient-reported outcome instrument that provides a measure of symptoms and physical limitations associated with heart failure. Assessments were based on the win ratio, which offers greater statistical power to detect and quantify a treatment difference by using all available information contained in the component outcomes.
Empagliflozin and clinical outcomes
A total of 530 patients with a median age of 71 years (34% women) were randomised to active treatment or placebo, within a median of 3 days after admission to hospital. The proportion of patients with diabetes ranged from 46.8% to 43.8%.
Overall, 33 (6.2%) of all patients died, 11 in the empagliflozin group and there were 67 patients assigned to empagliflozin who experienced at least one HFE. The adjusted mean change in KCCQ total score from baseline to 90 days was 36.2 in the empagliflozin group and 31.7 in the placebo arm. More patients taking empagliflozin had a clinical benefit compared to placebo (stratified win ratio = 1.36, 95% CI 1.09 – 1.68, p = 0.0054). This benefit was observed irrespective of the ejection fraction and for both de novo and decompensated heart failure in the presence or absence of diabetes.
The authors concluded that initiating empagliflozin as a component of usual clinical care for patients hospitalised with acute heart failure led to clinically meaningful benefits.
Voors AA et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med 2022
4th October 2021
As a drug class, the sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown in a systematic review to have a moderate effect on major adverse cardiovascular events in patients with established atherosclerotic cardiovascular disease. Moreover, the same review identified how SGLT2is can also reduce hospitalisation for heart failure (HF) and progression of renal disease regardless of existing atherosclerotic cardiovascular disease. In addition to these positive effects on cardiovascular outcomes, SGLT2is have been shown to reduce 24-hour blood pressure (BP) in diabetic patients. Nevertheless, this blood pressure-lowering effect is of concern in those with HF, especially as between 15 and 20% of HF patients have low systolic BP and therefore at a higher risk of in-hospital and post-discharge mortality.
In an effort to evaluate whether the baseline systolic BP affected outcomes associated with the use of empagliflozin, an international team, led by researchers from Saarland University, Germany, enrolled patients in the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction (EMPEROR-Reduced) trial. Patients with class II, III, or IV heart failure and an ejection fraction of less than 40% were randomised in a 1:1 fashion to either empagliflozin (10mg daily) or placebo in addition to their usual therapy for heart failure. For the study, patients were grouped according to their baseline systolic BP, as <110mmHg, 110–130mmHg or > 130mmHg and the primary outcome in the EMPEROR-Reduced trial was a composite of adjudicated cardiovascular death or hospitalisation for heart failure. For the present study, the researchers focused on whether the baseline systolic BP influenced the outcomes of cardiovascular death and hospitalisations for HF in patients given empagliflozin compared to placebo.
A total of 3730 patients were randomised to either empagliflozin (1863) or placebo and all patients had a left ventricular ejection fraction of less than 30%. Over a median of 16 months, the event rate per 100 patients years (pys) of follow-up, the primary outcome increased from 16.5 among the high SBP group to 20.8 for the intermediate group, and to 26.3 per 100 among the patients with low SBP (p=0.0015). Compared with placebo, treatment with empagliflozin significantly decreased the risk of cardiovascular death among the low systolic BP (hazard ratio, HR = 0.78, 95% CI 0.61–1.00), intermediate (HR = 0.71, 95% CI 0.58–0.87) and high (HR = 0.82. 95% CI 0.62–1.09) groups. However, while there were reductions in rates of HF hospitalisation with empagliflozin compared with placebo, this was only significant for patients with intermediate (110–130mmHg) systolic BP (HR = 0.66, 95% CI 0.50–0.88).
The authors concluded that empagliflozin reduced the risk of cardiovascular death and the number of HF hospitalisations and that this effect occurred independently of the baseline systolic BP.
Bohm M et al. Empagliflozin Improves Cardiovascular and Renal Outcomes in Heart Failure Irrespective of Systolic Blood Pressure. J Am Coll Cardiol 2021.