PVP-Guided Decongestive Therapy in HF 2 (PERIPHERAL-HF2)

Peripheral Venous Pressure-Guided Decongestive Therapy in Heart Failure 2

The investigators hypothesize that a simple assessment of peripheral venous pressure (PVP) will better predict the diuretic need and long-term outcomes (all cause mortality, all cause rehospitalization, emergency department visits) compared to standard evaluation.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Congestive Heart Failure; Congestion
• Intervention / Treatment: Drug: Diuretic therapy

Detailed Description

I. BACKGROUND AND SIGNIFICANCE

Precise assessment of volume status is essential in diagnosis and management of diuretic therapy in patients hospitalized for heart failure (HF). Unfortunately, no clear guidelines are present for in-hospital management of congestion. Consequently, nearly half of the patients hospitalized for congestive HF are discharged with persistent congestion. This contributes to high rates of readmission and mortality.

Recently, it has been shown that a simple assessment of peripheral venous pressure (PVP) demonstrates a high correlation with central venous pressure (CVP), indicating that PVP may be useful in the standard bedside clinical assessment of volume status in HF patients to help guiding decongestive therapy.

II. THE HYPOTHESIS

The main hypothesis is as follows: A simple assessment of peripheral venous pressure (PVP) will better guide the diuretic need and long-term outcomes (all-cause mortality, all cause re-hospitalization, emergency department visits) compared to standard evaluation.

III. METHODS

1. Application for Institutional Review Board (IRB)/Ethics board approval The study will be at participating centers. An IRB/Ethics board approval has been obtained from Marmara University, Pendik Training and Research Hospital local ethics board.
2. Study population Patients 18-99 years old who were admitted with a de novo or decompensated chronic HF and accept to participate in the study will be enrolled. Patients will be included regardless of ejection fraction or etiology of HF, but these will be noted as baseline variables. All patients or legal surrogate decision makers will be requested to provide a written informed consent prior to enrollment. Patients who withdraw their consent, those with upper extremity venous pathology, those with a baseline creatinine level equal to or above 3.5 mg/dL, those with severe stenotic valvular disease and hypertrophic cardiomyopathy will be excluded.
3. Data Collection The study will start at participating centers on July 1, 2024.

Baseline variables Baseline variables will be entered to the electronic study form (RedCap).

Procedures A peripheral intravenous (IV) access, using an 18 to 22-gauge IV line, will be placed preferably to an upper extremity vein before enrollment. This line will be used to draw blood samples first. After blood samples were collected the subjects will be randomized to standard or PVP guided therapy groups. Randomization will be done using a computer-generated random allocation list via RedCap randomization module. The details of demographic characteristics, symptoms, physical examination findings and drug list will be noted to a standard electronic study form (see appendix). A routine electrocardiogram and echocardiogram will be performed at the earliest convenience.

After the blood samples were collected, line will be flushed carefully. PVP will be obtained by transducing a peripheral intravenous line after zeroing at the phlebostatic axis. The phlebostatic axis will be accepted as the midpoint between the anterior and posterior surfaces of the chest at the level of the fourth intercostal space meets with sternum, which is assumed to be correlated with the mid-level of the right atrium. The patient's arm will be placed parallel to the patient such that the position of the peripheral IV to be at the phlebostatic axis. Continuity of the peripheral IV line with the central venous system will be confirmed by demonstrating augmentation of the venous pressure waveform using manual or tourniquet circumferential occlusion of the extremity proximal to the catheter and modified Valsalva maneuver. If the pressure waveform failed to augment appropriately, data will not be collected, and the patient will be documented for study purposes as a technique failure. Daily fluid intake and output, weight, and biochemistry measurements, as required, will be done.

The patients in whom the first and the predischarge PVP cannot be measured due to technical issues (unable to provide upper extremity IV access, unable to confirm augmentation or Valsalva test) will be excluded from the study. Also, the patients requiring in-hospital intubation, high-dose inotrope or vasopressor infusion (≥10 mcg.kg-1.min-1 dopamine, dobutamine or equivalent), intraaortic balloon support, dialysis or veno-venous ultrafiltration will be excluded from the study (but these patients will be included in the in-hospital analyses).

In hospital diuretic treatment will be guided by ESC guidelines (see references). In the standard therapy arm, the treatment and the decision of discharge will be left to physicians' discretion. In the PVP-guided arm, a PVP < 9 mmHg will be targeted before discharge.

Outcomes The primary outcome of the study is the composite endpoint of all-cause mortality, all-cause hospitalization and all-cause emergency department visits. The secondary outcomes will include cardiovascular mortality, HF-related hospitalization, HF-related emergency department visits. This information on these outcomes will be obtained from the national electronic database. The follow-up duration is planned to be limited to one year.

Predefined secondary analyses

There will be subanalyses from the same cohort, as defined below:

• The correlation between predischarge PVP and long-term outcomes. A multivariable analysis will also be executed for predicting the primary end point.
• The correlation between the change in PVP during hospital stay and long-term outcomes. A multivariable analysis will also be executed for predicting the primary end point.
• The correlation between the change in PVP during hospital stay and worsening renal function, renal injury, need for dialysis or veno-venous ultrafiltration.
• The comparison of the two arms in terms of worsening renal function, need for dialysis or veno-venous ultrafiltration.
• The comparison of the two arms in terms of EVEREST congestion score.
• The comparison of the two arms in terms of the days in hospital.
• The comparison of the two arms in terms of the number of repeat hospitalizations.
• Usual patterns of diuretic use

Estimated number of subjects to be submitted:

We estimated that the enrollment of 621 participants would provide the study with a statistical power of 95% to detect a relative risk reduction of 26% (hazard ratio [HR] = 0.74) for the composite primary outcome (PVP-guided group: 40%, standard approach: 50%), using a two-sided test at the 0.05 significance level. This calculation assumes a 10% censoring rate and a 1-year follow-up period. The weighted event rate (πe=45%) was used to estimate the required number of events. To account for potential loss to follow-up and ensure robust analysis, the sample size was increased to 650 participants, maintaining equal allocation between groups (1:1 randomization).

Statistical Analysis Baseline characteristics will be summarized using standard descriptive statistics. Comparisons of relevant parameters between groups will be performed by chi-square, Fisher's exact test, Mann-Whitney U and student t-test, as appropriate. Kaplan-Meier analysis will be performed to determine the cumulative long-term mortality and composite outcome rates in subgroups. The mortality across groups will be compared using log-rank test. A Cox-regression model will be used to perform a survival analysis according to pre-discharge peripheral venous pressure and composite outcome. Baseline characteristics with a P value of 0.05 or less in the univariate analysis will be included and a step-down procedure will be applied for selection of final covariates. Statistical analyses will be performed with SPSS (version 24.0; SPSS Inc., Chicago, IL) and MedCalc Software (version 18.2.1 [Evaluation version]; MedCalc Software, Ostend, Belgium).

• Study Type: Interventional
• Enrollment (Estimated): 650
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Emre K Aslanger, Prof; Phone Number: 21067‬ +90 (212) 909 60 00; Email: mr_aslanger@hotmail.com
• Study Contact Backup: Name: Özlem Yıldırımtürk, Prof; Email: ozlemyt@gmail.com

Study Locations

• Turkey
  • Ankara, Turkey, 6010
    • Recruiting
    • Ankara Etlik City Hospital
    • Contact: Belma Kalaycı, Assoc. Prof.; Phone Number: 0312 797 00 00; Email: drbelma@hotmail.com
    • Contact: Çağatay Tunca, MD
  • Antalya, Turkey, 07040
    • Recruiting
    • Antalya Ataturk State Hospital
    • Contact: Özgür Çağaç, MD; Phone Number: +90 242 3454550; Email: ozgurcagac@yahoo.com
  • Antalya, Turkey, 07070
    • Active, not recruiting
    • Akdeniz University
  • Edirne, Turkey, 22030
    • Recruiting
    • Trakya University
    • Contact: Cihan Öztürk, Asist. Prof.; Phone Number: +90 (284) 235 76 41; Email: dr.cihanozturk@gmail.com
  • Erzurum, Turkey, 25040
    • Recruiting
    • Erzurum Atatürk University Hospital
    • Contact: Oğuzhan Birdal, Assoc. Prof.; Phone Number: +90 (442) 344 66 66; Email: droguzhanbirdal@gmail.com
  • Eskişehir, Turkey, 26080
    • Recruiting
    • Eskişehir City Hospital
    • Contact: Ezgi Çamlı Babayiğit; Phone Number: +90 (222) 611 40 00; Email: ezgi_iel@hotmail.com
  • Istanbul, Turkey, 34303
    • Recruiting
    • Mehmet Akif Ersoy Training and Research Hospital
    • Contact: Ali K Kalkan, Prof; Phone Number: +90 (212) 692 20 00; Email: drakkalkan@gmail.com
    • Sub-Investigator: İrem Türkmen, MD
  • Istanbul, Turkey, 34668
    • Recruiting
    • Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital
    • Contact: Özlem Yıldırımtürk, Prof.; Phone Number: +902165424444; Email: ozlemyt@gmail.com
  • Istanbul, Turkey, 3440
    • Recruiting
    • Başakşehir Çam and Sakura City Hospital
    • Contact: Emre Aslanger, Prof; Phone Number: 21067 +902129096000; Email: mr_aslanger@hotmail.com
    • Contact: Özlem F Pamuk, MD; Phone Number: +902129096000; Email: kof.12@hotmail.com
    • Sub-Investigator: Yelda Saltan, MD
    • Sub-Investigator: Yaser İslamoğlu, MD
  • Istanbul, Turkey
    • Recruiting
    • Bağcılar Training and Research Hospital
    • Contact: Esra Dönmez, MD; Phone Number: 0 (212) 440 40 00; Email: dresradonmez@yahoo.com
    • Contact: Sevgi Özcan, MD; Phone Number: 0 (212) 440 40 00
  • Izmir, Turkey, 35665
    • Recruiting
    • Bakırçay University, Faculty of Medicine
    • Contact: Saadet Aydın, MD; Phone Number: +90(232) 493 00 00; Email: dr.saadetaydin@gmail.com
  • Kahramanmaraş, Turkey, 46700
    • Terminated
    • Pazarcık State Hospital
  • Kars, Turkey, 36100
    • Recruiting
    • Kafkas University Health Research and Application Hospital
    • Contact: Doğan İliş, Asist. Prof.; Phone Number: +90 (474) 225 21 06; Email: ilisdogan@hotmail.com
  • Kütahya, Turkey, 43100
    • Recruiting
    • Kütahya Health Sciences University
    • Contact: Taner Şen, Prof; Phone Number: +90 (274) 260 00 43; Email: medicineman_tr@hotmail.com
    • Contact: Mevlüt Demir, MD
    • Sub-Investigator: Emre B Erkip, MD
    • Sub-Investigator: Fevzican Doğru, MD
    • Sub-Investigator: Ahmet F Şahin, MD
  • Tokat, Turkey, 60030
    • Recruiting
    • Tokat Gaziosmanpasa University
    • Contact: Çağrı Zorlu, Asist. Prof.; Phone Number: +90 (356) 212 95 00; Email: zorlufb@hotmail.com
  • Şırnak, Turkey, 73300
    • Recruiting
    • İdil State Hospital
    • Contact: Barış Güven; Phone Number: +90 (486) 551 36 36; Email: guvenbariss@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

• Hospitalization for heart failure (de novo or decompensated chronic heart failure) irrespective of left ventricular ejection fraction
• Age 18-99
• Accept to participate

Exclusion criteria

• A prior history of upper extremity venous disease
• Serum creatinine ≥ 3.5 mg/dL
• Severe stenotic valvular disease
• Hypertrophic obstructive cardiomyopathy
• Withdrawal of consent
• Indwelling central venous catheter,
• Implanted left ventricular assist device
• History of heart transplantation
• Clinical diagnosis of cardiogenic shock
• Any right-to-left shunt

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PVP-Guided; Peripheral venous pressure guided diuretic therapy arm	Drug: Diuretic therapy; Diuretic therapy will be tailored according to peripheral venous pressure targets or standard approach
Active Comparator: Control; Standard dıuretic therapy arm	Drug: Diuretic therapy; Diuretic therapy will be tailored according to peripheral venous pressure targets or standard approach

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary end point: Major adverse events (Mortality and rehospitalization)	The difference in the combined rate of all-cause mortality, all-cause hospitalization and all-cause emergency department visits	One year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary combined end point:Major cardiac adverse events (Cardiac mortality and hospitalization)	The difference in the combined rate of cardiovascular mortality, HF-related hospitalization, HF-related emergency department visits.	One year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
PVP (discharge and delta) and long term outcomes	The correlation between predischarge the absolute amount of pre-discharge peripheral venous pressure (PVP in mmHg) and the change in PVP (in mmHg) during hospital stay and the rate of adverse long-term primary outcomes. (The higher the absolute PVP, more adverse outcomes is hypothesized. The higher the change in PVP during hospital stay, less the rate of adverse events is hypothesized). A multivariable analysis will also be executed for predicting the primary end point.	One year
PVP (delta and cohort) and in-hospital renal outcomes	The correlation between the change in PVP during hospital stay (in mmHg) and the rate of worsening renal function, renal injury, need for dialysis or veno-venous ultrafiltration.	One year
Congestion	The comparison of the two arms in terms of EVEREST congestion score (EVEREST congestion score, range 0-18, the higher the score, the higher the congestion (worse outcome))	One year
Hospital stay	The comparison of the two arms in terms of hospital stay (in days). Longer hospital stay duration is deemed as worse outome.	One year

Collaborators and Investigators

• Sponsor: Başakşehir Çam & Sakura City Hospital
• Collaborators: Ataturk University; Kutahya Health Sciences University; Akdeniz University; Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital; Eskisehir City Hospital; Ankara Etlik City Hospital; Istanbul Mehmet Akif Ersoy Educational and Training Hospital; Trakya University Faculty of Medicine; Bağcılar Training and Research Hospital; Bakırçay University, Faculty of Medicine; İdil State Hospital; Kafkas University Health Research and Application Hospital; Pazarcık State Hospital; Tokat Gaziosmanpaşa University, Faculty of Medicine
• Investigators: Principal Investigator: Emre K Aslanger, Prof, Basaksehir Pine and Sakura City Hospital; Principal Investigator: Özlem Yıldırımtürk, Prof, Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital

Publications and helpful links

General Publications

• Mullens W, Damman K, Harjola VP, Mebazaa A, Brunner-La Rocca HP, Martens P, Testani JM, Tang WHW, Orso F, Rossignol P, Metra M, Filippatos G, Seferovic PM, Ruschitzka F, Coats AJ. 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 Feb;21(2):137-155. doi: 10.1002/ejhf.1369. Epub 2019 Jan 1.

Helpful Links

• A preliminary study with a similar protocol from the same principal investigator (Akaslan, D., Aslanger, E., Saltan, Y., et al. Peripheral venous pressure guided decongestive therapy in HF. Eur J Heart F 2023; 125)

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2024
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: June 25, 2024
• First Submitted That Met QC Criteria: July 3, 2024
• First Posted (Actual): July 11, 2024

Study Record Updates

• Last Update Posted (Estimated): December 4, 2024
• Last Update Submitted That Met QC Criteria: December 1, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure; Physiological Effects of Drugs; Natriuretic Agents; Diuretics
• Other Study ID Numbers: BC&SSH-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD sharing may be considered upon personal application

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No