{"doi":"10.1002/ejhf.3159","title":"Reply to ‘Vasodilators in Congestive Heart Failure: The Perfect Weapon Aiming Just Off the Target?’","abstract":"We thank Dr Bocchino and colleagues for their interest in our mechanistic trial, which demonstrated that vasodilators, such as cimlanod, might attenuate diuresis in response to furosemide in patients with heart failure (HF), reduced left ventricular ejection fraction and congestion.1 Renal retention of salt and water is a key pathophysiological driver of symptoms, signs, organ dysfunction and adverse outcomes in HF2, and when it leads to a hospitalization, intravenous administration of loop diuretics is usually required, and recommended by guidelines. Our findings suggest that, despite a fall in total peripheral resistance and an increase in cardiac output, most patients with HF who are congested have little to gain from receiving a vasodilator and might be worse off if the vasodilator impairs diuresis. Contemporary registries indicate that up to 30% of patients hospitalized primarily due to an episode of acute HF (AHF) might be treated with vasodilators, perhaps as an adjunctive therapy to improve symptoms, predominantly in the setting of pulmonary oedema or severe hypertension.3 As pointed out by our colleagues, observational studies also suggest that vasodilators might improve haemodynamics and preserve renal function in patients with AHF who have a low cardiac output. However, while observational studies can provide valuable insights into prescribing patterns and potential correlations, they cannot establish a cause–effect relationship between use of vasodilator and outcomes. So far, there is no evidence from randomized trials that vasodilators improve outcomes in patients with AHF. In the GALACTIC trial, treatment with a combination of nitrates, hydralazine, and inhibitors of the renin–angiotensin–aldosterone system did not provide any clinical benefit compared to standard care, but did increase the risk of hypotension (8% vs. 2%) and delay reduction in body weight, perhaps reflecting impaired diuresis or lower tolerability of high doses of loop diuretics, or both; and there was no treatment interaction with renal function.4 These findings are consistent with the neutral effects seen with other vasodilators, like serelaxin, nesiritide or ularitide, in patients with AHF.5 We agree that our findings should not be generalized to all patients with AHF, for instance those with severe systemic hypertension. As we wrote in our paper, vasodilators might be used for 2–3 h for patients with severe breathlessness due to pulmonary oedema, in order to reduce left atrial pressure on the theoretical assumption that this will reduce lung water. However, evidence to back this theory is scant. Conducting randomized trials in patients who are only likely to benefit if treatment is introduced immediately during a crisis, which may happen at any time of day and will often resolve symptomatically within a 2–3 h window with standard care, is challenging. Currently, it seems wise to avoid the use of vasodilators in patients with AHF unless there is a very special reason for giving them and, when used, stopping them soon after the severity of breathlessness diminishes, or the blood pressure is adequately reduced. Rather, the focus should be on implementing guideline-recommended medical therapy as soon as appropriate. Our mechanistic trial design provides a useful clinical model to investigate the effects of adjunctive therapy on water and salt excretion in patients with HF and congestion. Such mechanistic trials do not require a large sample size, can be completed within a few months at modest cost and expose fewer patients to the risk of adverse events.","journal":"European Journal of Heart Failure","year":2024,"id":495224,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.953,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":262064,"name":"G. Michael Felker","orcid":"0000-0002-5931-1239","position":1,"is_corresponding":false},{"id":49635,"name":"John G.F. Cleland","orcid":"0000-0002-1471-7016","position":2,"is_corresponding":false},{"id":370039,"name":"Pierpaolo Pellicori","orcid":"0000-0001-7175-0464","position":0,"is_corresponding":true}],"reference_count":5,"raw_metadata":null,"created_at":"2026-07-19T02:09:15.528853Z","pmid":"38379019","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}