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Heart failure (HF) treatment has changed substantially over the last 30 years, leading to significant reductions in mortality and hospital admissions in patients with HF with reduced ejection fraction (HFrEF). Currently, the optimization of guideline-directed chronic HF therapy remains the mainstay to further improve quality of life, mortality, and HF hospitalizations for patients with HFrEF. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (S/V) has an important role in the treatment of patients with HFrEF. The PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) randomized controlled trial has established solid evidence for the treatment of HFrEF in various subgroups. Apart from HFrEF, several studies have been conducted using S/V in various indications: patients hospitalized with acute decompensated HF, HF with preserved ejection fraction, acute myocardial infarction with reduced ejection fraction, uncontrolled and resistant hypertension, and chronic kidney disease. Data from the German Institute for Drug Use Evaluation reveal that implementation of S/V has increased steadily over time and, by the end of 2021, an estimated 266 000 patients were treated with S/V in Germany. The estimated cumulative real-world patient exposure is >5.5 million patient-treatment years worldwide. The number of patients treated with S/V largely exceeds the number of patients treated in clinical trials, and the current indication for S/V is larger than the strict inclusion/exclusion criteria of the randomized trials. Especially elderly patients, women, and patients with more and more severe comorbidities are underrepresented in the clinical trials. We therefore aimed to summarize the importance of S/V in HF in terms of efficacy and safety in clinical trials and daily clinical practice., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Fourteen patients with supraventricular and/or ventricular ectopic beats selected by clinical, dynamic ECG and exercise test, underwent a basal continuous ECG recording (Holter) and then were given 400 mg of quinidine orally. The concentrations of the drug were determined in blood samples taken 30 minutes before, and 1, 2, 4, 6, 8, 12, and 24 hours after administration. On the same day patients were also monitored by continuous ECG recording (Holter). One week later, after a washout period, the same subjects were treated with 200 mg of quinidine orally 4 times a day for two weeks. On day 1, 2, 4, 7 and 14 quinidine was determined in plasma, and on day 7 and 14 a 24 hour ECG recording was also done. On the basis of pharmacokinetic parameters obtained from the acute test, the chronic levels of the drug were predicted. Predicted values were superimposable to those observed. Thus, the kinetics of single-dose quinidine is able to predict the steady-state levels after repeated dosing. During acute administration there was an increase in QTc interval and a decrease in ectopic beats. These effects correlated with a sigmoid pattern with acute quinidine levels. Concentrations producing 50% of the effect (EC50) could be calculated from these curves. In spite of similar steady-state blood levels of quinidine, some patients after chronic therapy did not respond to treatment (non responders). Non responders could be predicted by the acute test because they had greater EC50 values of QTc increase: patients with EC50 greater than 2 mg/L were all non responders.