Going With the Flow: Device Therapy for Heart Failure Complicated by Cardiorenal Syndrome

Cardiorenal syndrome (CRS) affects up to 40% of patients admitted with acute decompensated heart failure (ADHF).1Rangaswami J Bhalla V Blair JEA Chang TI Costa S Lentine KL et al.Cardiorenal syndrome: classification, pathophysiology, diagnosis, and treatment strategies: a scientific statement from the American Heart Association.Circulation. 2019; 139: e840-e878Crossref PubMed Scopus (612) Google Scholar Although the precise mechanisms driving ADHF-CRS at the neurohormonal and cellular levels have not been fully elucidated, is it clear that the syndrome results from complex, multifactorial pathophysiologies, inclusive of reciprocal and unfavorable hemodynamic interactions between the heart and kidneys,2Ross EA Congestive renal failure: the pathophysiology and treatment of renal venous hypertension.J Card Fail. 2012; 18: 930-938Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar along with neurohormonal activation and fibrotic structural changes that contribute to progressive cardiorenal dysfunction and congestion. Patients with persistent congestion at the time of discharge have a 40% likelihood of mortality at 90 days,3Wattad M Darawsha W Solomonica A Hijazi M Kaplan M Makhoul BF et al.Interaction between worsening renal function and persistent congestion in acute decompensated heart failure.Am J Cardiol. 2015; 115: 932-937Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar prompting urgent need to explore novel interventions aimed at treating CRS and achieving decongestion. Medical devices designed to treat patients with primarily cardiac-driven CRS (type 1–2) are in various phases of clinical study that aim to improve renal arterial perfusion directly (termed renal "pushers") or, secondarily, to reduce venous hypertension (termed renal "pullers") (Table 1). A detailed description of the proposed mechanisms of the benefits of CRS devices has been reported previously.4Nathan S Basir MB Emerging device therapies for cardiorenal syndrome.J Soc Cardiovasc Angiogr Intervent. 2023; 2101210Abstract Full Text Full Text PDF Scopus (1) Google Scholar,5Martens P Burkhoff D Cowger JA Jorde UP Kapur NK Tang WHW Emerging individualized approaches in the management of acute cardiorenal syndrome with renal assist devices.JACC Heart Fail. 2023; 11: 1289-1303Crossref PubMed Scopus (4) Google Scholar In brief, the puller devices act on central venous pressure by restricting caval venous return or increasing splanchnic vascular capacity through modulation of splanchnic innervation. By reducing renal venous pressures (microcirculatory renal afterload related to renal interstitial pressures), transrenal perfusion pressure (TRPP) (mean arterial pressure minus central venous pressure) is increased, thereby potentially facilitating improved renal function and diuretic response. However, the devices do not address renal malperfusion secondary to low cardiac output. In contrast, the renal pushers aim to augment renal blood flow by placement of a continuous-flow micropump just above the renal arteries. The potential benefits of renal pushers are intuitive for those with low-output states, but the benefit is less obvious when ADHF-CRS is driven primarily by congestion. A reduction in renal blood flow limits delivery of diuretics to the kidney, while a reduction in glomerular filtration limits tubular sodium delivery.5Martens P Burkhoff D Cowger JA Jorde UP Kapur NK Tang WHW Emerging individualized approaches in the management of acute cardiorenal syndrome with renal assist devices.JACC Heart Fail. 2023; 11: 1289-1303Crossref PubMed Scopus (4) Google Scholar,6Wilcox CS Testani JM Pitt B Pathophysiology of diuretic resistance and its implications for the management of chronic heart failure.Hypertension. 2020; 76: 1045-1054Crossref PubMed Scopus (66) Google Scholar It is hypothesized that selectively augmenting renal artery perfusion may reduce activation of the sympathetic nervous system at the level of the renal afferent artery and (simultaneously) lead to improved diuretic efficiency.5Martens P Burkhoff D Cowger JA Jorde UP Kapur NK Tang WHW Emerging individualized approaches in the management of acute cardiorenal syndrome with renal assist devices.JACC Heart Fail. 2023; 11: 1289-1303Crossref PubMed Scopus (4) Google Scholar,6Wilcox CS Testani JM Pitt B Pathophysiology of diuretic resistance and its implications for the management of chronic heart failure.Hypertension. 2020; 76: 1045-1054Crossref PubMed Scopus (66) Google ScholarTable 1Circulatory renal assist devicesPullers: Decrease Renal AfterloadAccess and PlacementMechanism of ActionPerfuser device (Nephronyx)Femoral vein; placed in inferior vena cavaCovered stent device increases flows and decreases pressures via the Bernoulli principle.Precardiac device (Abiomed)Internal jugular vein; placed in superior vena cavaIntermittent cycled balloon superior vena cava occlusion reduces venous inflow.Doraya Catheter (Revamp Medical)Femoral vein; placed in inferior vena cava below level of renal veinsPartial obstruction of venous flow; goal is to decrease cardiac preload and venous congestion.Aquadex system (Nuwellis)Aquapheresis via placement of a temporary dual lumen catheterReduces intravascular volume (reduces cardiac wall stress and renal afterload).Pushers: Increase Renal PreloadAortix pump (Procyrion)Femoral artery; placed in descending aorta at T10–T12 vertebraeIntra-aortic axial flow pump provides 3.5 L/min of flow.Retian pump (Cardiobridge)Femoral artery; placed in descending aorta 5–10 cm distal to the origin of the left subclavianPropeller system increases flow in the thoracic and abdominal aorta.ModulHeart pump (Puzzle Medical Devices)Femoral artery, placed in descending aorta at level of T11 vertebra3 axial flow pumps in parallel provide approximately 4 L/min of flow at 14,000 rpm.Second Heart Assist pump (Second Heart)Femoral artery, placed in descending aortaSelf-expanding stent-based impeller pump provides estimated 4–6 L/min of flow. Open table in a new tab Trials of CRS devices are expected to face challenges in terms of the identification of the optimal patient phenotype and clinically relevant endpoints that would define a device's success. This has been noted in trials examining ultrafiltration in heart failure. Thus, the field, in concert with the Food and Drug Administration, needs to consider the following points so we can enable the industry to demonstrate efficiently its niche in providing CRS support:1.What is the target population with ADHF for device therapy? Diuretic resistance has traditionally been a main focus for inclusion in current CRS trials. However, a uniformly accepted definition of diuretic resistance is lacking; some definitions focus on urinary response to a specific diuretic dosage, and others focus on urine sodium avidity and diuretic dosing.7Rahman R Paz P Elmassry M Mantilla B Dobbe L Shurmur S et al.Diuretic resistance in heart failure.Cardiol Rev. 2021; 29: 73-81Crossref PubMed Scopus (11) Google Scholar Additionally, diuretics have been shown to elicit neurohormonal activation that may negate the benefit of fluid losses achieved while being an inpatient, leading to rapid fluid retention upon hospital discharge and to diuretic inefficiency.2Ross EA Congestive renal failure: the pathophysiology and treatment of renal venous hypertension.J Card Fail. 2012; 18: 930-938Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar,5Martens P Burkhoff D Cowger JA Jorde UP Kapur NK Tang WHW Emerging individualized approaches in the management of acute cardiorenal syndrome with renal assist devices.JACC Heart Fail. 2023; 11: 1289-1303Crossref PubMed Scopus (4) Google Scholar Thus, there is the argument that demonstration of diuretic resistance prior to device-trial enrollment may not be imperative to demonstrate clinical benefit. If less ill patients with ADHF are enrolled, the trials would have to demonstrate clinical benefit without an increased risk of device-related complications and marked increase in cost.2.What is the optimal clinical trial endpoint? The field needs consensus concerning clinically relevant endpoints for therapies addressing ADHF-CRS. Improvement in hemodynamics and net fluid loss while on support should be noted, but are these endpoints alone sufficient? And should hemodynamic monitoring be required? What endpoint defines a successful renal response? True renal function early after decongestion is challenging to assess; creatinine elevations may reflect hemoconcentration. Finally, because devices would probably be adopted at centers without advanced heart failure surgical therapies, will an improvement in survival rates or readmission at 30 days, compared to the use of diuretics, be sufficient? Or does the field want to see a more durable impact on outcomes and cost effectiveness? In conclusion, the application of device therapies in the treatment of ADHF-CRS offers the potential to expand our treatment toolbox for patients with a complex disease process. Currently, the field awaits clinical trial data that demonstrate efficacy and safety and helps providers to identify the ideal patient phenotype for renal pusher vs renal puller therapy. Defining therapeutic success remains an important consideration. Ultimately, the value of CRS therapies will be contingent on safe deployment with reproducible and durable improvements in hemodynamics, congestion and renal function.