Lung Water by Ultrasound Guided Treatment in Hemodialysis Patients (The Lust Study).
Lung Water by Ultrasound Guided Treatment in Hemodialysis Patients (The Lust Study).
Volume overload is a leading risk factor for death and cardiovascular events in end stage
 renal disease patients maintained on chronic dialysis, particularly in those with myocardial
 ischemia and heart failure which represent a substantial fraction of this population. Early
 identification of volume overload may prevent cardiovascular sequel in these patients but
 clinical signs of volume expansion are unsatisfactory to reliably identify patients at risk
 and to monitor them over time. On the other hand, however reliable, standard techniques for
 measuring extracellular or circulating (blood) volume do not convey information on
 fundamental heart function parameters that determine the individual haemodynamic tolerance to
 volume excess and the response to ultrafiltration, i.e. left ventricular (LV) filling
 pressure and LV function.

 Extra-vascular lung water is critically dependent on these parameters and represents a proxy
 of both, circulating volume and LV filling pressure and function, and may therefore be a
 better criterion to identify patients at a higher risk of volume-dependent adverse clinical
 outcomes and to monitor the effect of therapy aimed at preventing these outcomes. A fast (< 5
 min.), easy to learn, simple and non-expensive technique which measures extra-vascular lung
 water by using standard ultrasound (US) machines has been validated in dialysis patients.
 Whether systematic measurement of lung water by this technique may translate into better
 clinical outcomes in End Stage Renal Disease (ESRD) patients has never been tested.

 The aim of this randomized clinical trial is that of testing a treatment policy guided by
 extra-vascular lung water measurements by ultrasound to prevent all-cause death,
 decompensated heart failure and non-fatal myocardial infarction in high risk dialysis
 patients with myocardial ischemia (a history of myocardial infarction with or without ST
 elevation or unstable angina, acute coronary syndrome documented by ECG recordings and
 cardiac troponins or stable angina pectoris with documented coronary artery disease by prior
 coronary angiography or ECG) or overt heart failure (NYHA class III-IV).
Randomization procedure: After enrollment, patients will be randomized in 2 groups: treatment
 and control. The randomization will be performed by centre, with a 1:1 allocation ratio, and
 it will be communicated by the coordinating centre in Reggio Calabria. An allocation
 concealment will be observed.

 Warning: based on the principle "once randomized, always randomized", if a patient drops out
 the study he cannot simply be replaced by a new one. New patients must be randomized as well.

 Validation of core lab data: The core data to be collected in the LUST project/subprojects
 should be validated by the following validation centres:

 -  CORE LUST STUDY DATA Echocardiographic data and US-lung data: Dr. Rosa Sicari and Dr.
 Luna Gargani, CNR Institute of Clinical Physiology of Pisa, Italy (rosas@ifc.cnr.it).

 -  ANCILLARY LUST PROJECTS Pulse Wave Velocity data (PWV): Prof. Gerard London, Service
 d'Hémodialyse, Hôpital F.H. Manhès, Fleury-Mérogis, France (glondon@club-internet.fr).

 24 Ambulatory Blood Pressure Monitoring (ABPM) data: Prof. Francesca Mallamaci,
 Nephrology, Dialysis and Transplantation Unit and IFC-CNR, Reggio Calabria

 Preliminary training on US-B lines measurement is a pre-requisite for Nephrologists and
 Cardiologists of each participating centre. After training (Skype meeting) an online
 certification will be released to certify the level of expertise about US-B lines
 measurements of all LUST study nephrologists and cardiologists.

 Each participant centre will upload pertinent studies (echocardiography, 24h ABPM and PWV
 data) into the LUST website and will timely receive a feedback by the validation centres,
 whenever needed.

 US Lung Scan technique A standard (3.0-MHz) echocardiography probe can be used for this
 purpose. Examinations should be performed in the supine position. To detect lung water, both
 sides of the chest should be scanned both in the anterior and lateral part from the second to
 the fourth (on the right side to the fifth) intercostals spaces, at parasternal, mid clavea,
 anterio-axillar and mid-axillary lines, as previously described (Am J Cardiol
 2004;93:1265-70). An US-B line is a hyperechoic, coherent US bundle at narrow basis going
 from the pleura to the limit of the screen. These extended lines (also called comets) arise
 from the pleural line and should be differentiated from short comets' artifacts that may
 exist in other regions. US-B lines starting from the pleural line can be either localized or
 scattered to the whole lung and be present either as isolated US-B lines or in groups (with a
 distance >7 mm between 2 extended comets). The sum of US-B lines produces a score reflecting
 the extent of LW accumulation. If you do not detect any US-B line, the score is 0.

 The investigators warn the physicians participating in the trial about fixed US-B lines, due
 not to lung water but to fibrosis or inflammatory processes. These comets should be
 registered but not counted as US-B lines. The cause that underlies these artefacts should be
 described.

 In patients allocated to the active arm of the study, any decision about weight reduction
 will be taken by Nephrologists only on the basis of pre-dialysis US-scans. However, also
 post-dialysis US-B lines measurement must be performed and registered. In the active and in
 the control arm as well, US-scans will be performed by the local cardiologist in coincidence
 with the echocardiographic study. It is crucial for the purpose of this study that
 cardiologists keep nephrologists involved in the LUST study blinded with respect to the
 number of US-B lines of patients of the control group.

 Timing

 -  In patients allocated to the control and the active arms, US-B lines should be performed
 at baseline and at 6, 12 and 24 months by the local cardiologist, in a non-dialysis day
 either on a Thursday or on a Friday, depending on the dialysis schedule.

 -  In patients allocated in the treatment arm, the application of US-B scans should be
 performed as follows:

 -  In patients with less than 15 US-B lines, ultrafiltration (UF) will not be modified and
 the US-B lines monitoring will be performed by the nephrologist at monthly intervals;

 -  In patients with more than 15 US-B lines (either at baseline or at any of the monthly
 US-B Lung scans) UF will be performed by scheduling longer and/or additional dialyses
 (see below). In these patients, monitoring of US pre-dialysis and post-dialysis -B lines
 will be repeated at least once a week, until the goal is achieved (see next section).

 -  Furthermore, in patients in the active arm, pre- and post-dialysis US-lung scans can be
 repeated at discretion of the nephrologist, i.e. whenever he/she believes that it can be
 useful applying this technique for monitoring the volume status of the patient, for
 example in a patient with <15 US-B lines who subsequently manifests a rise in body
 weight or in a patient who develops hypotension or frank hypotensive episodes during
 dialysis .

 In brief, in the treatment group, monitoring is scheduled once a week (before and after
 dialysis), or even more frequently if the nephrologist believes that a more frequent
 monitoring may be useful to track the desired UF goal. When the number of US-B lines falls
 below 15, the measurements will be repeated at monthly intervals.

 Weight reduction in patients with more than 15 US-B lines

 In patients randomized to the treatment arm and with a number of US-B lines >15, a decrease
 of dry weight is required to reduce lung water, according to the following scheme derived by
 a pilot study at the coordinating centre and at the Iasi Nephrology Unit:

 -  15-30 US-B lines: decrease dry weight by 300 g over the following week (about 100 g per
 session)

 -  31-40 US-B lines: decrease dry weight by 450 g over the following week (about 150 g per
 session)

 -  > 40 US-B lines: decrease dry weight by 600 g over next week (about 200 g per session).

 Attempts to lower dry weight according to the previous scheme should continue until the US-B
 lines goal (<15) is attained. If the patient does not tolerate attempts to decrease dry
 weight for 2 weeks (i.e. if he/she develops hypotension, cramps and other symptoms) extra
 haemodialysis sessions should be considered.

 If the goal (<15 pre-dialysis US B-lines) is not achieved after 4-6 weeks, or in case the
 patient does not tolerate UF, drug treatment (carvedilol, ACEi, ARB) intensification or
 introduction should be considered.

 Once the goal is achieved, it is recommended to confirm it by repeating the measurement of
 US-B lines at least once, for example before the following dialysis.

 Warnings:

 -  In patients in the active arm with initial pre-dialysis US-B lines <15 and in those who
 achieve this goal thanks to body fluids subtraction who develop cramps and/or symptoms
 of extracellular volume depletion (low dry weight) the decision of increasing dry weight
 should be accompanied by close US-B lines monitoring (i.e. every dialysis session until
 the patient stabilizes).

 -  In patients with >15 pre-dialysis US-B lines who do not tolerate dry weight decrease due
 to hypotension and who are on hypotensive/cardioprotective drugs treatment
 (carvedilol/ACEi) the dose of these drugs should be down-titrated and stopped, if
 needed. These drugs in these patients should be always given after dialysis (before
 going to bed, at night) rather than pre-dialysis.

 Clinical (pre-dialysis) evaluation of volume status In both groups (treatment and control
 group), a standard pre-dialysis clinical evaluation of volume status should be done, as it is
 recommended in good clinical practice. This evaluation should consider blood pressure and
 change of blood pressure over time, pedal edema, presence/absence of dyspnea, crackles on
 lung auscultation (see below), body weight gain inter-dialysis and body weight trajectory
 over time. In the active arm of the study these data should also be formally registered
 whenever US-B lines measurements are done. In the control group, evaluation of volume status
 needs to be formally registered only in coincidence of the echocardiographic studies.

 The following scale will be used for the evaluation of Crackles :

 1. No crackles

 2. I am uncertain about the presence of fine crackles

 3. Definite fine crackles at lung bases

 4. Moderate crackles

 5. Bilateral, diffuse crackles

 For clinical edema, the following scale will be used:

 1. No clinical edema

 2. Slight pitting (2 mm depth) with no visible distortion

 3. Somewhat deeper pit (4 mm) with no readily detectable distortion

 4. Noticeably deep pit (6 mm) with the dependent extremity full and swollen

 5. Very deep pit (8 mm) with the dependent extremity grossly distorted

 Echocardiographic measurements In both the intervention and control arm, cardiologists
 involved in the LUST study will perform the echocardiographic measurements at baseline, 6, 12
 and 24 months, in a non-dialysis day on a Thursday or on a Friday, depending on the dialysis
 schedule. These echocardiogram are "research echocardiograms". For this reason, it is
 fundamental to keep nephrologists blind about the results of these echocardiographic
 readings.

 Nevertheless, nephrologists are allowed to consult a cardiologist (be him the LUST
 cardiologist or another one) for a "clinical echocardiogram" if and when clinical problems
 arise which demand the application of echocardiographic studies for diagnostic reasons or for
 monitoring any underlying cardiac problem.

 Detailed information about standardization of echocardiographic study has been prepared by
 echocardiography validation laboratory (Dr. Rosa Sicari and Dr. Luna Gargani, IFC CNR, Pisa).

 Statistical analysis plan A total sample size of 500 patients (250 per group) will be
 expected to provide approximately 80% power to detect a difference in the primary end point
 with an assumed type I error rate of .05, 2-sided.Investigators estimate that the 2 year
 event rate for the composite end point would be 45% in the usual care group and 30% (a 33%
 risk reduction) in the arm with the lung US-guided intervention. According to protocol, all
 patients will be followed for 24 months after randomization.

 Survival analysis will be performed by the Kaplan-Meier and the Cox regression methods.
 Missing baseline categorical variables will be replaced with the mean or median value, as
 appropriate. The effect of the allocation arm on the number of US-B lines will be
 investigated by Linear Mixed Models (LMM).

 The between arms differences in echocardiographic data (secondary end point) will be compared
 by T-Test, Mann-Whitney test and Linear Model Analysis, as appropriate.

 A secondary analysis of the longitudinal evolution of US B lines and the time to the first
 event and to repeated events will be performed by the Joint Models. All analyses will be
 based on the principle of intention to treat and will be performed using the SPSS version 24,
 STATA version 13. The threshold for statistical significance will be 2 sided with a type I
 error rate of .05.
Inclusion Criteria:

 -  Age > 18 years

 -  Dialysis vintage > 3 months

 -  A history of myocardial infarction with or without ST elevation or unstable angina,
 acute coronary syndrome, documented by ECG recordings and cardiac troponins, or stable
 angina pectoris with documented coronary artery disease by prior coronary angiography
 or ECG or dyspnoea class III-IV NYHA

 -  Written consent to take part in the study

 Exclusion Criteria:

 -  Cancer or other advanced non cardiac disease or comorbidity (e.g. end-stage liver
 failure) imposing a very poor short-term prognosis

 -  Active infections or relevant inter-current disease

 -  Inadequate lung scanning and echocardiographic studies