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
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.
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.
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).