Many thanks for these helpful comments—we would like to comment on them as follows:
With regard to the blockade of the renin-angiotensin-aldosterone system (RAAS), PD Matthes addresses an important point: Evidence on its effect on the prognosis of patients with heart failure has primarily been established for ACE inhibitors. The available data on AT1 receptor antagonists (ARBs) are less conclusive (compare Table 2; ). Consequently, ACE inhibitors should be the preferred treatment for patients with heart failure; ARBs should only be used in patients with intolerance to ACE inhibitors, especially because of coughing. We also agree with the second point he makes: The combination of an ARB and a neprilysin inhibitor is a “compromise” in respect to the evidence related to RAAS inhibition. The underlying cause is the accumulation of bradykinin which is associated with an increased risk of severe angioedema in patients with simultaneous inhibition of ACE and neprilysin (see Box; ). The initially evaluated combination of ACE inhibitor and neprilysin inhibitor (substance name: omapatrilat), however, was not superior to enalapril in patients with heart failure (OVERTURE study)—unlike sacubitril/valsartan in the PARDIGM-HF trial. For this reason—and because of the significantly higher rates of angioedema in patients receiving omapatrilat (2)—this substance was not further investigated as a treatment for heart failure and is not approved for this indication.
Prof. Mertens addresses a key point in the treatment of patients with chronic heart failure: Many patients have (multiple) comorbidities—especially chronic renal failure which is common in daily clinical practice and of prognostic relevance. The administration of mineralocorticoid receptor antagonists (MRAs) increases the risk of hyperkalemia. Thus, the dose of spironolactone should only be increased to 50 mg/d in patients with intact renal function and/or if electrolyte levels are regularly monitored—especially in the light of the common concomitant administration of further RAAS inhibitors (ACE inhibitors, ARBs, sacubitril/valsartan). Otherwise, the low-dose regimen should be maintained or, if necessary, the dose should be further reduced. Here, it should be mentioned that the current guidelines of the European Society of Cardiology (ESC) recommend doses of spironolactone and eplerenone of up to 100 to 200 mg/d if no additional RAAS inhibitor is administered (3). According to our assessment, the dose of 50 mg/d should typically not be exceeded in the treatment of heart failure. In some cases, hyperkalemia associated with reduced renal function prevents dose escalation in the treatment of heart failure. In the future, this situation may improve with the use of enteral potassium binders, such as patiromer. However, further studies are needed to show that the administration of patiromer improves dose titration of heart failure medications and thus achieves relevant effects on prognosis.
In their letter, Dr. Langheim and Prof. Schwaab address the important point of cardiac rehabilitation. The related evidence has already been presented by them based on current international guidelines. Since our task was to write a CME article on pharmacotherapy and device-based therapies of heart failure, we have not specifically discussed rehabilitation, but we would like to emphasize here the importance of these measures.
In comparison with the treatments which we described in detail in our article, the available evidence on the treatment with diuretics is rather scarce. This is also highlighted by Dr. Burkhardt in his letter. During the review process of the CME article, the aim was to highlight treatments with sound evidence base. Not least due to the limited word count, it was necessary to focus the article on these therapies. Nevertheless, there is no doubt that diuretic therapy is of fundamental importance as a large portion of heart failure patients require treatment with diuretics. An excellent review was already cited in the comment (4). The supplement to the ESC’s 2016 guidelines for the diagnosis and treatment of acute and chronic heart failure (Web Table 7.7) provides a concise presentation of the use of diuretics which is very relevant for clinical practice (3).
Dr. med. Dominik Berliner
Prof. Dr. med. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Conflict of interest
Dr. Berliner received consultancy fees from Novartis. He received funds for the preparation of scientific meetings from Orion Pharma, Abbott Vascular, and Novartis Pharma GmbH. He received funds to conduct clinical trials from Zoll Medical Corporation, CVRx, and Novartis..
Prof. Bauersachs received consultancy fees from Astra Zeneca, Bayer, BMS, Böhringer Ingelheim, Novartis, Servier, and Vifor. He was reimbursed for travel and accommodation costs by Bayer, Böhringer Ingelheim, and Servier. He received funds for the preparation of scientific meetings from Abiomed, Astra Zeneca, Bayer, BMS, Böhringer Ingelheim, CVRX, Medtronic, MSD, and Novartis He received funds for a research project of his own initiation as well as to conduct clinical trials from Abiomed, Bayer, Böhringer Ingelheim, CVRX, Medtronic, MSD, Vifor, and Zoll.
|1.||Berliner D, Hänselmann A, Bauersachs J: The treatment of heart failure with reduced ejection fraction. Dtsch Arztebl Int 2020; 117: 376–86 VOLLTEXT|
|2.||Packer M, Califf RM, Konstam MA, et al.: Comparison of omapatrilat and enalapril in patients with chronic heart failure: the omapatrilat versus enalapril randomized trial of utility in reducing events (OVERTURE). Circulation 2002; 106: 920–6 CrossRef MEDLINE|
|3.||Ponikowski P, Voors AA, Anker SD, et al.: 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016; 18: 891–975 CrossRef MEDLINE|
|4.||Mullens W, Damman K, Harjola VP, et al.: The use of diuretics in heart failure with congestion – a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019; 21: 137–55 CrossRef CrossRef|