Biomarkers

ISSN: 1354-750X (Print) 1366-5804 (Online) Journal homepage: http://www.tandfonline.com/loi/ibmk20

Rationale and Design of the IMPACT EU-trial:

Improve Management of Heart Failure with
Procalcitonin Biomarkers in Cardiology (BIC) - 18

Martin Möckel, Anna Slagman, Jörn Ole Vollert, Stefan Ebmeyer, Jan C.
Wiemer, Julia Searle, Evangelos Giannitsis, John A. Kellum & Alan Maisel

To cite this article: Martin Möckel, Anna Slagman, Jörn Ole Vollert, Stefan Ebmeyer, Jan C.
Wiemer, Julia Searle, Evangelos Giannitsis, John A. Kellum & Alan Maisel (2017): Rationale
and Design of the IMPACT EU-trial: Improve Management of Heart Failure with Procalcitonin
Biomarkers in Cardiology (BIC) - 18, Biomarkers, DOI: 10.1080/1354750X.2017.1420823

To link to this article: https://doi.org/10.1080/1354750X.2017.1420823

Accepted author version posted online: 21

Dec 2017.

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 Rationale and Design of the IMPACT EU-trial:

Improve Management of Heart Failure with Procalcitonin

Biomarkers in Cardiology (BIC) - 18

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Martin Möckel, MD, PhD1; Anna Slagman, VD, MSc1; Jörn Ole Vollert, MD, MBA2;Stefan

Ebmeyer, MD2; Jan C. Wiemer, PhD 2; Julia Searle, MD, MPH1; Evangelos Giannitsis, MD,

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PhD3, John A. Kellum, MD, MCCM 4 , Alan Maisel, MD5

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Division of Emergency Medicine and Chest Pain Units, Campus Charité Mitte and Campus
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Virchow Klinikum, Charité – Universitätsmedizin Berlin, Germany, 2Thermo Fisher

Scientific, Clinical Diagnostics, B•R•A•H•M•S GmbH , Hennigsdorf, Germany, 3Department

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of Angiology, Cardiology and Pneumology, University Hospital Heidelberg, Germany;

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Department of Critical Care Medicine, University of Pittsburgh, PA, USA; 5Coronary Care

Unit and Heart Failure Program, Veterans Affairs San Diego Healthcare System, UCSan
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Diego School of Medicine, San Diego, CA, USA

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Running title: IMPACT-EU Study Design (BIC-18)

Total word count: 3.775 words

Funding: The study is sponsored by Thermo Fisher Scientific, Clinical Diagnostics,

BRAHMS GmbH. JOV, JCW and SE are employees of Thermo Fisher Scientific.
 Relationship with industry: AS and JS report grants from Thermo Fisher Scientific during the

conduct of the study; JOV, JCW and SE are employees of Thermo Fisher Scientific. EG reports

personal fees from Thermo Fisher Scientific BRAHMS GmbH during the conduct of the study; MM

reports grants and personal fees from Thermo Fisher Scientific during the conduct of the study. JAK

reports grant support and consulting fees from Alere. AM report research support, speaking, and

consulting with Thermo Fisher Scientific (moderate amount).

Address for correspondence:

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Martin Möckel, MD, PhD

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Charité – Universitätsmedizin Berlin, Division of Emergency Medicine CVK, CCM

Augustenburger Platz 1, 13353 Berlin, Germany

Tel: +49 30 450 553 307 Fax: +49 30 450 7 553307

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E-Mail: martin.moeckel@charite.de
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 Abstract
Objectives To evaluate the effectiveness of Procalcitonin (PCT)-guided antibiotic treatment

compared to current treatment practice to reduce 90-day all-cause mortality in emergency

patients with shortness of breath (SOB) and suspected acute heart failure (AHF).

Background Concomitant AHF and lower respiratory tract (or other bacterial) infection in

emergency patients with dyspnea are common and can be difficult to diagnose. Early and

adequate initiation of antibiotic therapy (ABX) significantly improves patient outcome, but

superfluous prescription of ABX maybe harmful.

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Methods In a multicenter, prospective, randomized, controlled process trial with an open

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intervention, adult emergency patients with SOB and increased levels of natriuretic peptides

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will be randomized to either a standard care group or a PCT-guided group with respect to the
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initiation of antibiotic treatment. In the PCT-guided group the initiation of antibiotic therapy

is based on the results of acute PCT measurements at admission, using a cutoff of 0.2 ng/ml.
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A two-stage sample-size adaptive design is used; an interim analysis was done after

completion of 50% of patients and the final sample size remained unchanged. Primary
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endpoint is 90-day all-cause mortality.

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Conclusions The current study will provide evidence, whether the routine use of PCT in
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patients with suspected AHF improves outcome.

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Key Words: acute heart failure (AHF), Procalcitonin (PCT), antibiotic therapy.
 Clinical Significance

IMPACT-EU is a multicenter, prospective, randomized, controlled process trial with an open

intervention evaluating the effectiveness of Procalcitonin (PCT)-guided antibiotic treatment

compared to current treatment practice to reduce 90-day all-cause mortality in a European

population of emergency patients with shortness of breath (SOB) and suspected acute heart

failure (AHF). Adult emergency patients with SOB and increased levels of natriuretic

peptides will be randomized to either a standard care group or a PCT-guided group with
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respect to the initiation of antibiotic treatment. Primary endpoint is 90-day all-cause mortality.

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This study will show whether PCT should be used as a standard biomarker in the primary

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assessment of AHF patients.

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 Abbreviations
ABX Antibiotic treatment

(A)HF (Acute) heart failure

MR-proANP Mid-regional pro-atrial natriuretic peptide

BACH Biomarkers in Acute Heart Failure

(NT-pro)BNP N-terminal-pro-B-type natriuretic peptide

DSRC Data safety review committee

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ED Emergency Department

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LRTI Lower respiratory tract infection

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PCT Procalcitonin

SOB Shortness of breath

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 Introduction

Study Background

Shortness of breath (SOB) is common among patients who present to the emergency

department (ED). In the CHARITEM study, which analyzed data from over 34,000 non-

surgical emergency patients, 7.4 % presented to the ED with the chief complaint dyspnea (1).

The most frequent diagnoses amongst emergency patients with dyspnea are acute heart failure

(AHF) and lower respiratory tract infections (LRTI) with overlapping signs and symptoms.

Additionally, the same patient may suffer from both, AHF and LRTI. The detection of
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superimposed LRTI in patients with AHF is challenging because of the non-specific nature of

chest X-ray results and conventional blood tests. LRTI substantially increase the risk of

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mortality in patients with HF (2, 3). A population based cohort study of 33,736 patients

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evaluated the association between preexisting HF and 30-day mortality in patients with first
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time hospitalization for pneumonia. Results suggest that patients with a preadmission history

of HF had a higher risk of mortality from pneumonia (24.4%) compared to those without
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(14.4%) (4). A sub-analysis of the PROTECT-trial was recently able to show that AHF

patients without clear signs and symptoms of infection but elevated PCT-values above 0.2
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ng/ml were more often classified as treatment failures and had a significantly increased risk
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for 30-day all-cause mortality(5).

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Blood levels of procalcitonin (PCT) reflect the presence and severity of bacterial infection (6-

9). Randomized-controlled trials have demonstrated that a clinical algorithm including PCT
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to guide antibiotic therapy decision in sepsis and LRTI is safe and effective (6, 10-15). Only a

small number of studies evaluate PCT-levels in patients with heart failure and there is even

less evidence on PCT-guided antibiotic therapy in AHF patients. These studies have been

summarized recently(16).Results of the BACH study (17) demonstrate that PCT levels

improve diagnostic accuracy in identifying pneumonia in patients with acute HF. In this

study, PCT significantly added to the diagnostic value of chest X-ray for the diagnosis of
 pneumonia, increasing the AUC from 0.80 to 0.86. Multivariate analysis combining PCT with

clinical signs demonstrated that PCT independently adds to overall diagnostic accuracy in

identifying pneumonia. The study highlights the potential use of PCT levels in guiding

antibiotic therapy in patients with AHF. It was demonstrated that in patients with PCT levels

>0.21 ng/ml, the lack of antibiotic therapy resulted in worse survival. Similarly, patients had

an elevated risk of mortality when treated with antibiotics if PCT levels were <0.05

ng/ml(17).

Study Objective
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The IMPACT-EU study evaluates a strategy of PCT-guided ABX prescription over

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established treatment practice with respect to 90-day all-cause mortality in a European

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population of patients presenting to an ED with a chief complaint of SOB and suspected AHF.
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 Methods
Study design

IMPACT-EU is a multicenter, international, prospective, randomized, controlled trial with an

open intervention. Patients are randomized 1:1 via a center-stratified, balanced and blocked

randomization procedure to either a standard care group or a PCT-guided group with respect

to the initiation of an antibiotic treatment. The study design is illustrated in figure 1. In the

standard care, PCT blind group, initiation and discontinuation of antibiotic therapy are

performed according to the physician’s intent to treat based on the patient’s routinely
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available medical information. PCT levels are not available to the treating staff. In the PCT-

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guided group the initiation of antibiotic therapy is based on the results of acute PCT

measurements at admission in addition to routinely available medical information. Further

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blood samples for PCT measurement are collected on day 1 (12-24 h after first blood draw) in
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both groups. PCT levels are used to guide antibiotic therapy according to an algorithm as

outlined in table 1. In both study groups, type and administration route as well as dosing
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regimen and duration of antibiotic therapy is at the discretion of the treating physician.
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Study population

The study enrolls consecutive, adult patients who present to one of the participating study
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centers with SOB and other signs and symptoms suggestive of AHF. The inclusion and
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exclusion criteria are listed in table 2. It is planned to enroll a total number of 792 patients.

Case numbers are unchanged after the interim analysis after completion of 50% of patients
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was performed (adaptive study design). By September 30, 2017, 685 patients were enrolled at

15 study sites.

Endpoints:

The primary endpoint is the 90-day all-cause mortality rate. The 30-day all-cause mortality

rate, hospital all-cause readmission within 30 days and diagnosis of pneumonia during the

index hospitalization will be assessed as secondary endpoints. Additionally, a number of

 exploratory endpoints will be analyzed (number of patients on antibiotic treatment, duration

of initial antibiotic therapy, hospital length of stay, ICU length of stay, need for second

line/additional antibiotic therapy and in-hospital pulmonary complications other than

pneumonia).

Procalcitonin measurement:

PCT is measured from sample tubes as by standard practice (serum or plasma), either with the

B•R•A•H•M•S PCT sensitive KRYPTOR as described in the instruction manual or with the

PCT assay available for routine testing at the respective study sites. Other assays than the
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B•R•A•H•M•S PCT sensitive KRYPTOR had to be approved by the steering committee to

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guarantee comparability of the PCT-results. Up to now only Roche Cobas PCT and Siemens

Advia Centaur were used in addition to the KRYPTOR.

Sample size calculation:

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90-day mortality rate was estimated by applying stratified Cox regression to BACH study data

(17, 18) yielding 18% mortality for the standard of care group and 11% mortality for the PCT-
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guided group (selection criteria: EU patients with MRproANP>300pmol/l), about 36% of

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these patients had elevated PCT on admission or 24 hours later) (table 3). Based on a two-

sided chi-square test for two independent proportions 396 subjects per arm would be
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sufficient to detect this 7% difference in mortality at 5% significance level with a power of

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80% in a study design with fixed sample size. Also, 396 patients per study arm yield 80% and

81% power to detect the estimated difference in mortalities at 5% significance level with Cox
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proportional hazards regression (Wald test of regression coefficient, hazard ratio calculated

assuming exponential survival distribution) and log-rank test (power calculation according to

Freedman), respectively. A two-stage sample-size adaptive design according to Bauer and

Köhne (19) is used in this study. The final sample size was calculated based on the results of

the interim analysis using log-rank test and Cox proportional hazards regression. After

finalization of the interim analysis whose results were blinded to the investigators, the DSRC
 recommended to finalize the study using initially calculated case numbers. No safety issues

were detected.

Statistical analysis:

The Intention to Treat (ITT) analysis as well as the Safety-Population will include all

randomized patients. For the per Protocol (PP) analysis all patients without major protocol

deviations during study participation will be included, who were treated according to the PCT

algorithm in the PCT-guided group, and who did not have PCT measurement results within

12 hours of presentation to the ED in the standard of care group.

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In a sensitivity analysis, a second PP analysis will be conducted expanding the PCT-guided

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group of the PP population to all PCT-guided patients without major protocol deviations and

with PCT measured on day 0.

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The first analytical step will be a thorough description of the overall study sample and the two
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randomized groups. The study sample will be described with frequency counts for nominal

variables and means with standard deviations or medians and inter-quartile ranges for
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numerical variables as appropriate to the distributional properties of variables. Standard uni-

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and bivariate statistics will be applied to check the success of randomization.

Primary study hypotheses are

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• Null hypothesis H0: No difference in 90-day all-cause mortality rate between the PCT
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guided group and standard care group.

• Alternative hypothesis H1: The 90-day all-cause mortality rate of the PCT guided group
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differs from the mortality rate of the standard care group.

The primary study hypotheses will be evaluated using log-rank test and Cox proportional

hazards regression of 90-day all-cause mortality rate (death, alive) concerning standard of

care group and PCT guided group. The centers will be included in this analysis as covariates

in accordance with the “Guideline on adjustment for baseline covariates” (20).

 A significance level of 5% will be used to test if the hazard ratio (HR) for the “treatment”-

factor is different from one. To conclude a statistically significant reduction in 90-day all-

cause mortality rate for the PCT-guided group, the regression coefficient has to be

significantly different from zero and negative, when defining the standard care group as the

reference. Statistical analysis will be conducted in two steps in accordance with the sample-

size adaptive design.

Safety analyses:

A Data Safety and Review Committee (DSRC) is responsible for ongoing, independent
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review of patient’s safety and correct and timely execution of the processes described in the

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protocol. Furthermore deviations from the PCT-guided treatment recommendations are

monitored by the DSRC, to detect issues related to the proposed treatment schedule. The

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DSRC conducted their first study safety assessment after 198 patients (25% of the originally
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planned sample size) have completed the 90 days follow up.

The second meeting of the DSRC held after 396 patients (50% of the planned sample size)
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have completed the 90 days follow up and coincided with the efficacy interim analysis (see
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below). The DSRC decided to have one further meeting after 75% of the patients have

completed their 3 months follow up.

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Interim analysis:
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After data of 396 patients were available (50% of the planned total population), an interim

analysis was performed with clean data of the primary endpoint.

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The primary study null hypotheses H0 was analyzed using log-rank test and Cox proportional

hazards regression (two-sided statistical testing of study arm regression coefficient) at an

adjusted alpha level of 0.0038.

Implications of the results of the interim analysis are shown in table 4. No premature stopping

of the study due to acceptance of the null hypothesis at the interim analysis was planned.
 As no significance was reached at this interim stage, the sample size for the study could have

been adapted for the second part of the study according to Bauer and Köhne (17) at 5%

significance level and with reasonable (e.g. 80%) statistical power on the basis of effects as

observed for the interim dataset. In accordance with the DSRC recommendation, the

originally planned sample size of 396 patients per study arm was maintained. Investigators

were blinded to the detailed results.

Second and final analysis:

The second part of the dataset comprising all study patients not yet included in the interim
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analysis will be analyzed by a second log-rank test and Cox proportional hazards regression

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(two one-sided statistical tests of study arm regression coefficient) using an adjusted type 1

error probability of α = 0.0038 / p(1), where p(1) is the one-sided p-value obtained during the

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interim analysis adjusted for the direction of the effect (in order to come to a correct
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conclusion on the outcome). This corresponds to two-sided statistical testing at the 5%

significance level for the entire study comprising the interim and the final analysis. Details of
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the analysis will be given in the statistical analysis plan.

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Secondary and exploratory study endpoints of the final study dataset will be analyzed by data

visualization, descriptive statistics, and further statistical hypothesis testing, e.g. by log-rank
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test, chi-square test, Fisher’s exact test, Mann-Whitney U-Test, and by Cox proportional
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hazards regression, logistic regression and multivariate methods as appropriate. Depending on

quality control findings (e.g. concerning missing data and censored observations) and on the
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success of randomization (balance of study arms concerning clinical covariates), additional

multivariate methods will also be applied to adjust the main analysis for potential

confounders.

Ethical considerations:

The IMPACT-EU trial complies with the Declaration of Helsinki. The Ethics committee of

the leading study center has approved the study (Ethics committee of the Charité –
 Universitätsmedizin Berlin EA4/025/16). All patients give their written informed consent

prior to enrollment and randomization. The trial was registered before enrollment of the first

patient (ClinicalTrials.gov, NCT02392689).

Current status:

IMPACT recruitment started in May 2015 (first patient in at Charité Berlin 6th May 2015). By

30th September 2017, 685 patients were enrolled at 15 recruiting study sites. One further site

is expected to start recruitment soon. Current patient numbers meet the expected recruitment

rate, interim analysis was conducted in May 2017, and, the last patient will be enrolled by
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June 2018 (figure 2).

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 Discussion
The IMPACT-EU trial is the first randomized controlled trial to compare a PCT-guided

antibiotic treatment strategy with the current standard of care in patients with AHF. The trial

addresses two important clinical needs: Diagnosis of co-existing (predominantly pulmonary)

infection in patients with AHF and adequate antibiotic medication in the ED and the hospital.

Previous studies implicate that PCT has the potential to help with differential diagnosis and

with guidance of antibiotic therapy.

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PCT-guided antibiotic therapy

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The concept of PCT-guided antibiotic treatment decisions has been tested previously. Christ-

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Crain et al. tested this strategy in two randomized interventional trials in patients with

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suspected LRTI and in community-acquired pneumonia and were able to significantly reduce
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antibiotic overuse (6, 10). The same study group also published results from the ProHosp trial,

a larger scale randomized interventional trial including 1359 patients with suspected LRTI
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who were randomly assigned to standard or PCT-guided antibiotic treatment. Use of antibiotic

medication and consequently side effects from antibiotic treatment were, again, significantly
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reduced (13).
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Analysis of PCT data in the observational BACH trial on the use of PCT for the diagnosis of
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(pulmonary) infection in the patients group with confirmed AHF showed that inadequate

antibiotic medication in patients with low PCT values as well as inadequate lack of antibiotic
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medication in patients with high PCT-values affected patient outcome (17). Similar results

were then shown in a sub-analysis of ProHosp patients with HF, where the subgroup of

patients with a low PCT value clearly profited from a PCT-guided strategy, indicating that

inadequate antibiotic treatment might affect patient outcome (21). Both trials evaluating the

concept in patients with HF are sub-analyses in an observational cohort and in a post-

randomization cohort respectively and do not provide enough evidence for conclusive results.
 PCT in heart failure:

Study results suggest that PCT levels might per se be elevated in patients with HF and

peripheral edema (22), possibly due to altered gut permeability of edematous intestines,

followed by bacterial translocation and endotoxin release into the blood stream (23-25). A

large study from China showed that the diagnostic value of PCT for infection in their cohort

was altered with increasing severity of co-existing HF (26).

On the other hand, Maisel et al. in the BACH trial used a PCT cut-off value of ≥0.21 ng/ml to
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identify patients who could profit from antibiotic treatment. This cut-off value is slightly

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below the standard cut-off value routinely used to guide antibiotic treatment in patients with

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LRTI in most laboratories and hospitals (0.25 ng/ml). The value was chosen on the basis of

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BACH-data on 90-day risk, as patients in the first PCT quintile (<0.05 ng/mL) had a 90-day
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survival rate of 92.0%, whereas patients in the fifth quintile (>0.21 ng/mL) had a survival rate

of only 80.5% (hazard ratio 2.6) (17).

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Schütz et al., in their ProHosp-subanalysis on PCT-guided antibiotic treatment in AHF-

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patients, used a similar cut-off value (0.25 ng/ml) to recommend antibiotic treatment and a

cut-off value of 0.5 ng/ml to strongly recommend antibiotic treatment (21). Demissei et al., in
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their sub-analysis of the PROTECT-trial, used the same cut-off as was identified in the
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BACH-study of 0.2 ng/ml to compare post-discharge outcomes of AHF-patients without clear

symptoms of infection with and without elevated PCT-levels. In their analysis, patients with
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PCT-values above 0.2 ng/ml had a significantly higher 30-day all-cause mortality (5). Alba et

al. recently identified an even lower PCT level of 0.1 ng/ml as the optimal cut-off to predict

one-year mortality in a pooled sample (PRIDE and BIONICS-HF) of 453 emergency patients

with dyspnea, of whom 47% had a diagnosis of HF, 6.5% of pneumonia and 6.5% were

diagnosed with both. When analyzing patients with a definite diagnosis of HF only, the cut-
 off needed to be 0.4 ng/ml though, to achieve 97% specificity (27). The cut-off for IMPACT-

EU was chosen on the basis of the BACH-trial, as this is the best evidence provided to date.

The actual HF guidelines of the ESC(28) state: “Assessment of procalcitonin levels may be

considered in patients with AHF with suspected coexisting infection, particularly for the

differential diagnosis of pneumonia and to guide antibiotic therapy, if considered.”

Correspondingly, an international experts paper highlighted the meaning of infection and the

challenges of correct early diagnosis, which requires interdisciplinary care(29).

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Conclusions

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Given the increasing incidence of AHF, and the increasing prevalence of multi-drug

resistance, it is mandatory to be able to determine which dyspneic patients have AHF,

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bacterial infection, or both. Previous studies have provided encouraging, but yet insufficient
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results, which need to be validated in a prospective, randomized trial.
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The current study will provide evidence, whether the routine use of PCT in patients with

suspected AHF according to the proposed algorithm improves outcome.

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 Clinical perspective

Medical knowledge

Patients with AHF and combined pulmonary infection are difficult to diagnose. Misdiagnoses

affect patient outcome.

Translational Outlook

Observational trials and sub-analyses have shown that PCT-guided and therefore adequate

antibiotic treatment improves outcome of patients with acute dyspnea and pulmonary
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infection including patients with AHF. A PCT-guided treatment strategy for patients with HF

needs to be tested in a randomized controlled trial before clinical implementation can be

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considered.

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 References
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20. Committee for Medicinal Products for Human Use (CHMP). Guideline on adjustment

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21. Schuetz P, Kutz A, Grolimund E, et al. Excluding infection through procalcitonin

testing improves outcomes of congestive heart failure patients presenting with acute
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175:464-72.

22. Niebauer J, Volk HD, Kemp M, et al. Endotoxin and immune activation in chronic

heart failure: a prospective cohort study. Lancet 1999; 353:1838-42.

23. Mann DL. Inflammatory mediators in heart failure: homogeneity through

heterogeneity. Lancet 1999; 353:1812-3.

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24. Anker SD, Egerer KR, Volk HD, Kox WJ, Poole-Wilson PA, Coats AJ. Elevated

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26. Wang W, Zhang X, Ge N, et al. Procalcitonin testing for diagnosis and short-term

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J Med 2016; 129:96-104.

28. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and

treatment of acute and chronic heart failure: The Task Force for the diagnosis and

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of the ESC. Eur Heart J 2016; 37:2129-200.

29. Mueller C, Christ M, Cowie M, et al. European Society of Cardiology-Acute

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 Figure legends

Figure 1.

Illustration of the IMPACT-EU study design as outlined in the text. ABX, antibiotic

treatment.

Figure 2.

Current (blue line) and expected (orange line) patient recruitment for the IMPACT-EU trial.
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Recruitment started in May 2015 and is expected to finish in June 2018.

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 Table 1: Decision rules for PCT-guided treatment
Day 0 (Admission to the ED):

PCT level is > 0.2 ng/ml Antibiotic therapy should be initiated

PCT level is ≤ 0.2 ng/ml Antibiotic therapy should not be initiated

Day 1 (12-24 h after first blood

draw):

PCT level is > 0.2 ng/ml Antibiotic therapy should be initiated or continued

PCT level is ≤ 0.2 ng/ml Antibiotic therapy should not be initiated, however
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should be continued as planned if initiated on day 0.

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Decision rules for procalcitonin (PCT)-guided antibiotic treatment in the IMPACT-EU trial.

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 Table 2: In- and Exclusion criteria

Inclusion criteria Exclusion criteria

- Adult patients who present to - Patient participates in any other interventional clinical

the ED with the leading trial

symptom dyspnea - Trauma related SOB

- Suspected or known HF - Patient diagnosed with lung or thyroid cancer

- MR-proANP>300 pmol/L, - Known terminal disease with life expectancy of less than 6

BNP>350 ng/l or NT- months, e.g. advanced metastasized cancer disease

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proBNP>1800 ng/l - Organ transplant requiring immunosuppression

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- Patient has given written - Abdominal, vascular or thorax surgery within the last 30

informed consent within study days

timelines to allow antibiotic

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- End stage/advanced HF – defined by planned heart
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therapy within 8 hours transplantation, or cardiogenic shock

- Hospitalization for at least 1 - Female patients who have given birth within 3 months
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overnight stay planned before study enrolment, pregnant or lactating women

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- Current use of antibiotics or requirement of immediate

antibiotic therapy before randomization and measurement

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- End stage renal failure requiring dialysis

- Patient is not willing, or it is not possible or advisable for

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the patient, to follow the study schedule, including

antibiotic therapy and 90 days follow up

- Patient has already participated in the clinical trial

previously

- Patients who are institutionalized by official or judicial

 order

- Dependents of the sponsor, the CRO, the study site or the

investigator

Inclusion and exclusion criteria of the IMPACT-EU trial. CRO, contract research
organization; ED, emergency department; SOB, shortness of breath; HF, heart failure; PCT,
procalcitonin.
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 Table 3: PCT-levels, antibiotic treatment and mortality in the BACH-trial
Data PCT Antibiotic No. of No. of No. of 90-day mortality

treatment patients events survivors subgroup PCT- total

(ABX) stratified

>0.2 ABX 53 15 38 28.3% 24.1%

BACH no ABX 88 19 69 21.6% 13.3%

≤0.2 ABX 81 18 63 22.2% 9.6%

no ABX 327 21 306 6.4%

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>0.2 ABX 29 12 17 41.4% 36.0%

BACH- no ABX 46 15 31 32.6% 18.4%

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EU ≤0.2 ABX 47 15 32 31.9% 12.9%

no ABX 194 16 178

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>0.2 ABX 24 3 21 12.5% 10.6%

BACH- no ABX 42 4 38 9.5% 6.4%

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US ≤0.2 ABX 34 3 31 8.8% 4.8%

no ABX 133 5 128 3.8%

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IMPACT-EU procalcitonin (PCT) levels, antibiotic treatments and mortalities based on the
reference dataset from BACH Study(18). BACH enrolled 549 patients corresponding to the
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IMPACT study protocol (BNP > 350 ng/l), 316 patients from EU, 233 patients from US. The
mortality in the EU-group was estimated to be approximately18 % in the standard arm, as
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antibiotic therapy was administered without PCT-guidance in BACH (see highlighted cells in
the table); treatment improvement potential for EU patients by PCT-guidance: prevention of
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15 deaths with PCT > 0.2µg/l & no antibiotic treatment and 15 deaths with PCT <=0.2µg/l
and (superfluous) antibiotic treatment.
 Table 4: Interim-Analysis scenarios
Result Implication

Scenario 1 Rejection of null hypothesis: Study to be stopped

p(1) ≤ 0.0038 Statistically significant superiority or inferiority
of the PCT-guided study arm over the standard
of care arm has been established;

Scenario 2 No conclusion about null hypothesis can be Decision by sponsor and PIs
p(1) > 0.0038 drawn as yet: if the study is to be
Recalculation of final study sample size based on continued
effect size estimates from the interim analysis.
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Result implications of the interim analysis in IMPACT-EU. PI, principal investigator.

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Meanwhile the interim analysis was done and decision was to continue the study without
adjustment of the case numbers.

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