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Joanna Osmanska, Mark C Petrie, Ross T Campbell, Reply: subcutaneous furosemide patch: heart failure decongestion ‘from the comfort of your home’, European Heart Journal - Cardiovascular Pharmacotherapy, Volume 10, Issue 3, April 2024, Pages 261–262, https://doi.org/10.1093/ehjcvp/pvae015
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We thank Dr Dimitriadis and colleagues for their comments1 on our report of 2 early phase studies reporting on a novel preparation of subcutaneous (SC) furosemide.2 We share their enthusiasm for further randomized clinical trials (RCTs) assessing the effectiveness of this novel drug-device combination in patients with heart failure (HF). The design and methods of early phase clinical trials investigating pharmacokinetic (PK) and pharmacodynamic (PD) parameters of new pharmaceuticals are stipulated by the U.S. Food and Drug Administration (FDA). While we agree that clinical endpoints are of the primary interest to clinicians, we followed this FDA guidance on Bioavailability and Bioequivalence Studies.3 Dr Dimitriadis and colleagues highlight the lack of blinding in our trials. Due to the nature of treatments and routes of administration, both trials were by necessity open label, however the primary outcome measures were objective. Measurements of PK/PD parameters (SQIN-Furosemide PK/PD trial) were conducted and reported by blinded laboratory technicians, and all statistical analyses of PK/PD results were performed by a blinded statistician. The lack of blinding of study treatment could not have resulted in bias pertaining to the primary endpoints.
We agree that weight change is a useful surrogate marker of effectiveness of treatment for decongestion. We have used this metric as the primary endpoint in another clinical trial assessing different diuretic regimes.4 However, the purpose of these early phase trials was not to test the clinical utility of this drug-device combination as a strategy for decongestion, but to firstly test the pharmacological properties of the novel preparation and, secondly, the safety and utility of the bespoke patch-pump. We did not report the change in weight in the primary manuscript, as change in weight was not a prespecified endpoint.2 We have now presented change in weight and serum electrolytes in Table 1. The change in weight was consistent with the diuresis and natriuresis already described.2 None of the participants developed a significant deterioration in renal function (defined in the protocol of the SQIN-Furosemide/abdominal device trial as eGFR decrease by ≥30% from the baseline or increase in serum creatinine ≥221 umol/L).
| . | SQIN-Furosemide PK/PD trial . | SQIN-Furosemide/abdominal device trial . | ||
|---|---|---|---|---|
| . | SC furosemide . | IV furosemide . | P value . | SC furosemide . |
| Weight change, kg | −1.3 (−2.8 to −0.8) | −1.1 (−1.7 to −0.6) | 0.35 | −1.5 (−2.8 to −0.9) |
| Potassium, mmol/L | −0.1 (−0.3 to 0.1) | 0 (−0.1 to 0.2) | 0.24 | −0.1 (−0.1 to 0.2) |
| Creatinine, mg/dL | 0.12 (0.07–0.22) | 0.09 (0.01–0.12) | 0.11 | |
| Creatinine, mmol/L | 1.5 (−2.5–8) | |||
| . | SQIN-Furosemide PK/PD trial . | SQIN-Furosemide/abdominal device trial . | ||
|---|---|---|---|---|
| . | SC furosemide . | IV furosemide . | P value . | SC furosemide . |
| Weight change, kg | −1.3 (−2.8 to −0.8) | −1.1 (−1.7 to −0.6) | 0.35 | −1.5 (−2.8 to −0.9) |
| Potassium, mmol/L | −0.1 (−0.3 to 0.1) | 0 (−0.1 to 0.2) | 0.24 | −0.1 (−0.1 to 0.2) |
| Creatinine, mg/dL | 0.12 (0.07–0.22) | 0.09 (0.01–0.12) | 0.11 | |
| Creatinine, mmol/L | 1.5 (−2.5–8) | |||
Results presented as median (IQR).
| . | SQIN-Furosemide PK/PD trial . | SQIN-Furosemide/abdominal device trial . | ||
|---|---|---|---|---|
| . | SC furosemide . | IV furosemide . | P value . | SC furosemide . |
| Weight change, kg | −1.3 (−2.8 to −0.8) | −1.1 (−1.7 to −0.6) | 0.35 | −1.5 (−2.8 to −0.9) |
| Potassium, mmol/L | −0.1 (−0.3 to 0.1) | 0 (−0.1 to 0.2) | 0.24 | −0.1 (−0.1 to 0.2) |
| Creatinine, mg/dL | 0.12 (0.07–0.22) | 0.09 (0.01–0.12) | 0.11 | |
| Creatinine, mmol/L | 1.5 (−2.5–8) | |||
| . | SQIN-Furosemide PK/PD trial . | SQIN-Furosemide/abdominal device trial . | ||
|---|---|---|---|---|
| . | SC furosemide . | IV furosemide . | P value . | SC furosemide . |
| Weight change, kg | −1.3 (−2.8 to −0.8) | −1.1 (−1.7 to −0.6) | 0.35 | −1.5 (−2.8 to −0.9) |
| Potassium, mmol/L | −0.1 (−0.3 to 0.1) | 0 (−0.1 to 0.2) | 0.24 | −0.1 (−0.1 to 0.2) |
| Creatinine, mg/dL | 0.12 (0.07–0.22) | 0.09 (0.01–0.12) | 0.11 | |
| Creatinine, mmol/L | 1.5 (−2.5–8) | |||
Results presented as median (IQR).
We share Dr Dimitriadis and colleagues’ enthusiasm and optimism for the use of novel devices to potentially aid the delivery of acute HF care in ambulatory settings. Indeed, the patch-infusor that we describe in our report, is one such device. We agree caution is needed before incorporating novel devices into clinical workflows, and devices require adequate testing, ideally in RCTs. The current evidence to support the use of invasive devices and transcutaneous sensors to detect congestion and electrolytes abnormalities in patients with acute decompensation of HF is limited. For example, while there is evidence to support the use of CardioMEMS HF in ambulatory patients with chronic HF, none of the trials examined the role of the CardioMEMS HF device in acute decompensation of HF or as tool to guide decongestion and diuretic therapy.5,6 We have designed, and are actively recruiting patients into, a multicentre RCT (NCT05419115), which will test the use of the novel furosemide/patch-infusor combination in a clinical pathway setting. This follow on trial will hopefully fill gaps in the current evidence base highlighted by Dr Dimitriadis and colleagues.
Conflict of interest: J.O. has no disclosures relevant to the contents of this paper.
M.C.P. has received research funding from Boehringer Ingelheim, Roche, SQ Innovation Inc, AstraZeneca, Novartis, Novo Nordisk, Medtronic, and Boston Scientific, Pharmacosmos. Consultancy and Trial committees: Boehringer Ingelheim, Novartis, Astra Zeneca, Novo Nordisk, Abbvie, Bayer, Takeda, Corvia, Cardiorentis, Pharmacosmos, Siemens, Vifor, and Director of Global Clinical Trial Partners (GCTP).
R.T.C. has received consultancy fees from Boehringer Ingelheim and speaking honorarium from AstraZeneca.
Data availability
The data underlying this article will be shared on reasonable request to the corresponding author.
