A Prospective Evaluation of Natriuretic Peptide Based Referral of CHF Patients in Primary Care

Chronic Heart Failure (CHF) Clinical Trial

— PREFER  

Official title:

A Prospective Evaluation of Natriuretic Peptide Based Referral of CHF Patients in Primary Care

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02807857
• Other study ID #: CLCZ696B3402
• Secondary ID: 2016-000473-20
• Status: Completed
• Phase: N/A
• Start date: July 7, 2016
• Est. completion date: March 23, 2018

Study information

• Verified date: February 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This low interventional study, whose unique intervention was to measure the blood level of a biomarker called NT-proBNP in chronic heart failure patients daily followed-up by Primary Care Physicians (PCPs) in Europe, assessed if the cardiologist referral guided by NT-proBNP measurement in patients who were currently judged by PCPs as being stable, would lead to optimization of HF treatment, defined in adherence to treatment recommendations of the current European Society of Cardiology guidelines for the treatment of heart failure.

Description:

In the majority of European countries, the primary management of chronic heart failure patients was performed by General Practitioners in collaboration with cardiologists (specialists). Previous studies had shown that many patients suffering from CHF do not receive optimal pharmacological and/or device treatment for their disease. An increase in natriuretic peptides (BNP, NT-proBNP) was associated with increased risk of cardiovascular events in heart failure patients. The purpose of the present study was to assess if a referral of clinical stable chronic heart failure patients with reduced ventricular ejection fraction (EF < or = 40%) and NT-proBNP level > or = 600 pg/mL to a specialist (cardiologist) led to treatment optimization, defined as adherence to the treatment recommendations according to the European Society of Cardiology (ESC) guidelines. In addition, data obtained in this study was used to describe demographic, clinical (including NT-proBNP levels) and treatment characteristics of CHF patients who were managed in the primary care setting across Europe..

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1415
• Est. completion date: March 23, 2018
• Est. primary completion date: March 23, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Willing and able to provide written informed consent and accept study procedures and time schedule.
• Age = 18 years.
• Patients suffering from chronic heart failure (the heart failure diagnosis must have been made or confirmed by a cardiologist and/or hospital physician at any time in the patient's medical history).
• Patients with reduced ejection fraction (= 40%) as confirmed at any time point in the patient's medical history.

Exclusion Criteria:

• Use of investigational drugs either within 5 half-lives of enrollment, or within 30 days, or until the expected pharmacodynamic effect has returned to baseline, whichever is longer.
• Major surgery in the last 3 months prior to baseline or planned major surgery or cardiac intervention during the study.
• Cancer or other significant co-morbidities implying that the patient's condition is unstable.
• Comorbidities that can be associated with elevated natriuretic peptide (NP) levels:

renal insufficiency, (eGFR < 25 ml/min/1.73 m² calculated according to MDRD formula), recent (less than 3 months) cerebral trauma or recent (less than 3 months) cerebrovascular incident, novel diagnosis or acute exacerbation of COPD within the last 3 months.

• Patients who are primarily managed and regularly followed-up by a cardiologist for their HF
• Highly frail patients whose estimated lifespan due to comorbidities by the judgement of the investigator is less than 6 months.

Related Conditions & MeSH terms

• Chronic Heart Failure (CHF)
• Heart Failure

Intervention

Procedure:
• Standard care
Patients will receive the treatment that their primary care physician has decided to prescribe for their disease

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Aarschot
Belgium	Novartis Investigative Site	Alveringem
Belgium	Novartis Investigative Site	Binkom	BEL
Belgium	Novartis Investigative Site	Boezinge
Belgium	Novartis Investigative Site	Bruxe
Belgium	Novartis Investigative Site	Buggenhout, Belgium
Belgium	Novartis Investigative Site	Deinze
Belgium	Novartis Investigative Site	Deurne
Belgium	Novartis Investigative Site	Diksmuide
Belgium	Novartis Investigative Site	Ezemaal-Neerwinden
Belgium	Novartis Investigative Site	Gozee	BEL
Belgium	Novartis Investigative Site	Hasselt
Belgium	Novartis Investigative Site	Hasselt, Belgium
Belgium	Novartis Investigative Site	Herzele
Belgium	Novartis Investigative Site	Kluisbergen
Belgium	Novartis Investigative Site	Landen
Belgium	Novartis Investigative Site	Leefdaal
Belgium	Novartis Investigative Site	Linkebeek
Belgium	Novartis Investigative Site	Linkebeek	BEL
Belgium	Novartis Investigative Site	Lommel
Belgium	Novartis Investigative Site	Maasmechelen
Belgium	Novartis Investigative Site	Mont sur Marchienne
Belgium	Novartis Investigative Site	Nazareth
Belgium	Novartis Investigative Site	OOsteeklo
Belgium	Novartis Investigative Site	Oostende
Belgium	Novartis Investigative Site	Oostham	BEL
Belgium	Novartis Investigative Site	Oudenaarde
Belgium	Novartis Investigative Site	Saint-Medard
Belgium	Novartis Investigative Site	Stoumont
Belgium	Novartis Investigative Site	Tessenderlo
Belgium	Novartis Investigative Site	Thuilles
Belgium	Novartis Investigative Site	Tielt-Winge
Belgium	Novartis Investigative Site	Tremelo
Belgium	Novartis Investigative Site	Vilvoorde
Belgium	Novartis Investigative Site	Waregem
Belgium	Novartis Investigative Site	Zichem	BEL
Croatia	Novartis Investigative Site	Bizovac
Croatia	Novartis Investigative Site	HRV
Croatia	Novartis Investigative Site	HRV
Croatia	Novartis Investigative Site	HRV
Croatia	Novartis Investigative Site	HRV
Croatia	Novartis Investigative Site	Krasica
Croatia	Novartis Investigative Site	Osijek
Croatia	Novartis Investigative Site	Rijeka
Croatia	Novartis Investigative Site	Rijeka	HRV
Croatia	Novartis Investigative Site	Slavonski Brod
Croatia	Novartis Investigative Site	Velika Kopanica
Croatia	Novartis Investigative Site	Viskovo
Croatia	Novartis Investigative Site	Visnjevac	HRV
Croatia	Novartis Investigative Site	Zagreb	HRV
Croatia	Novartis Investigative Site	Zagreb
Cyprus	Novartis Investigative Site	Nicosia
Cyprus	Novartis Investigative Site	Nicosia
Denmark	Novartis Investigative Site	Præstø
Denmark	Novartis Investigative Site	Skive
Estonia	Novartis Investigative Site	Paide
Estonia	Novartis Investigative Site	Someru	EST
Estonia	Novartis Investigative Site	Tallinn
Estonia	Novartis Investigative Site	Tallinn
Estonia	Novartis Investigative Site	Tallinn
France	Novartis Investigative Site	Arras
France	Novartis Investigative Site	Bersee
France	Novartis Investigative Site	Breteuil Sur Seine
France	Novartis Investigative Site	Cannes
France	Novartis Investigative Site	Chantepie
France	Novartis Investigative Site	Colombiers
France	Novartis Investigative Site	Coursan
France	Novartis Investigative Site	Erquy
France	Novartis Investigative Site	La Seyne-sur-Mer
France	Novartis Investigative Site	Laval
France	Novartis Investigative Site	Les Pennes Mirabeau
France	Novartis Investigative Site	Negrepelisse
France	Novartis Investigative Site	Orthez
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Rosiers d'Egleton
France	Novartis Investigative Site	Salles
France	Novartis Investigative Site	Six Fours
France	Novartis Investigative Site	St orens de Gameville
France	Novartis Investigative Site	Strasbourg
Hungary	Novartis Investigative Site	Balatonkeresztur
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Csongrad
Hungary	Novartis Investigative Site	Erd
Hungary	Novartis Investigative Site	Felsorajk
Hungary	Novartis Investigative Site	Hosszuheteny
Hungary	Novartis Investigative Site	Kecskemet
Hungary	Novartis Investigative Site	Korondi
Hungary	Novartis Investigative Site	Nyiregyhaza
Hungary	Novartis Investigative Site	Pecs
Hungary	Novartis Investigative Site	Szabadsag
Hungary	Novartis Investigative Site	Szeged-Szoreg
Hungary	Novartis Investigative Site	Szekesfehervar
Hungary	Novartis Investigative Site	Torokbalint
Hungary	Novartis Investigative Site	Zakanyszek
Israel	Novartis Investigative Site	Beer Sheva
Italy	Novartis Investigative Site	Gatteo	FC
Italy	Novartis Investigative Site	Grumello Del Monte	BG
Latvia	Novartis Investigative Site	Jelgava	LVA
Latvia	Novartis Investigative Site	Riga	LVA
Latvia	Novartis Investigative Site	Riga
Latvia	Novartis Investigative Site	Riga
Latvia	Novartis Investigative Site	Riga
Lithuania	Novartis Investigative Site	Alytus
Lithuania	Novartis Investigative Site	Kaunas
Lithuania	Novartis Investigative Site	Kaunas
Lithuania	Novartis Investigative Site	Kaunas	LTU
Lithuania	Novartis Investigative Site	Kaunas	LTU
Lithuania	Novartis Investigative Site	Klaipeda	LTU
Lithuania	Novartis Investigative Site	Vilnius
Malta	Novartis Investigative Site	Rabat
Malta	Novartis Investigative Site	Xaghra	Gozo
Malta	Novartis Investigative Site	Xewkija	Gozo
Norway	Novartis Investigative Site	Flisa
Norway	Novartis Investigative Site	Hamar
Norway	Novartis Investigative Site	Honefoss
Norway	Novartis Investigative Site	Kirkenær
Norway	Novartis Investigative Site	Lierskogen
Norway	Novartis Investigative Site	Lørenskog
Norway	Novartis Investigative Site	Loten
Norway	Novartis Investigative Site	Noetteroey
Norway	Novartis Investigative Site	Ostereidet
Norway	Novartis Investigative Site	Skien
Poland	Novartis Investigative Site	Bialystok
Poland	Novartis Investigative Site	Bialystok
Poland	Novartis Investigative Site	Bielawa
Poland	Novartis Investigative Site	Bydgoszcz
Poland	Novartis Investigative Site	Chelm	POL
Poland	Novartis Investigative Site	Dzierzoniow
Poland	Novartis Investigative Site	Kartuzy	POL
Poland	Novartis Investigative Site	Katowice
Poland	Novartis Investigative Site	Krakow
Poland	Novartis Investigative Site	Krakow
Poland	Novartis Investigative Site	Krakow
Poland	Novartis Investigative Site	Lublin
Poland	Novartis Investigative Site	Miasteczko Slaskie
Poland	Novartis Investigative Site	Poznan
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Warszawa	POL
Poland	Novartis Investigative Site	Wielen
Poland	Novartis Investigative Site	Wroclaw
Poland	Novartis Investigative Site	Zgierz
Portugal	Novartis Investigative Site	Cantanhede
Portugal	Novartis Investigative Site	Leca da Palmeira
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Oeiras
Portugal	Novartis Investigative Site	Seixal	Bairro Novo
Russian Federation	Novartis Investigative Site	Kazan
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Petrozavodsk
Russian Federation	Novartis Investigative Site	Saint Petersburg
Russian Federation	Novartis Investigative Site	St.- Petersburg
Russian Federation	Novartis Investigative Site	Ufa
Russian Federation	Novartis Investigative Site	Vladivostok
Russian Federation	Novartis Investigative Site	Yaroslavl
Slovenia	Novartis Investigative Site	Ivancna Gorica
Slovenia	Novartis Investigative Site	Kranj
Slovenia	Novartis Investigative Site	Ljubljana
Slovenia	Novartis Investigative Site	Maribor
Slovenia	Novartis Investigative Site	Pesnica pri Mariboru
Slovenia	Novartis Investigative Site	Slovenske Konjice
Slovenia	Novartis Investigative Site	Spodnji Duplek
Slovenia	Novartis Investigative Site	Vrhnika
Slovenia	Novartis Investigative Site	Zalec
Spain	Novartis Investigative Site	A Estrada	Pontevedra
Spain	Novartis Investigative Site	Alcudia	Islas Baleares
Spain	Novartis Investigative Site	Alicante
Spain	Novartis Investigative Site	Burriana	Castellon
Spain	Novartis Investigative Site	Cambre	A Coruna
Spain	Novartis Investigative Site	Coruna
Spain	Novartis Investigative Site	El canaveral	Caceres
Spain	Novartis Investigative Site	El Parador De Las Hortichiuela	Almeria
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Monteporeiro	Pontevedra
Spain	Novartis Investigative Site	Oviedo	Asturias
Spain	Novartis Investigative Site	Oviedo	Asturias
Spain	Novartis Investigative Site	Panxon
Spain	Novartis Investigative Site	Parla	Madrid
Spain	Novartis Investigative Site	Petrer	Alicante
Spain	Novartis Investigative Site	Porto do Son	A Coruña
Spain	Novartis Investigative Site	Puerto Real	Cadiz
Spain	Novartis Investigative Site	Telde	Las Palmas De Gran Canaria

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Belgium,  Croatia,  Cyprus,  Denmark,  Estonia,  France,  Hungary,  Israel,  Italy,  Latvia,  Lithuania,  Malta,  Norway,  Poland,  Portugal,  Russian Federation,  Slovenia,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Clinically Stable Patients Whose Therapy Regimen Adheres to ESC Guideline Recommendations for Drug Types (Level 1) and Drug Type and Dose (Level 2) at Visit 1 (Before Referral to a Cardiologist)	Assessment of treatment regimen with respect to ESC guideline adherence at Visit 1 before referral to cardiologist. ESC Criteria for adherence: Drug Types: Treatment with (1) ACEi or (1) ARB in combination with (1) beta-blocker and (1) MRA for patients w/an LVEF = 35% at V1. Treatment w/(1) ACEi or (1) ARB, in combination with (1) beta-blocker+ without treatment with an MRA for patients with an LVEF > 35% at visit 1. Drug type & dose: Guideline adherent with respect to drug types and dosage of all respective guideline drugs = 50% of the recommended target dose.	Baseline (Visit 1)
Primary	Adherence to ESC Guideline at Visit 2 (After Referral to a Cardiologist, Month 6), for Follow-up Set: Drug Type and Drug Type and Dose	Assessment of patients' adherence at Visit 2, for patients who were already adherent at Visit 1, and those who were not adherent at Visit 1, for both drug type and drug type and dose. ESC Criteria for adherence: Drug Types: Treatment with (1) ACEi or (1) ARB in combination with (1) beta-blocker and (1) MRA for patients w/an LVEF = 35% at V1. Treatment w/(1) ACEi or (1) ARB, in combination with (1) beta-blocker+ without treatment with an MRA for patients with an LVEF > 35% at visit 1. Drug type & dose: Guideline adherent with respect to drug types and dosage of all respective guideline drugs = 50% of the recommended target dose.	Month 6
Secondary	Duration of Heart Failure	The duration of Heart Failure was collected at Baseline (Visit 1).	Baseline (Visit 1)
Secondary	Number of Patients With Current Use of Concomitant Compound	Use of concomitant compounds were collected at baseline (Visit 1)	Baseline (Visit 1)
Secondary	Number of Follow-Up Patients With Current Use of Concomitant Compound at Visit 2	Use of concomitant compounds were collected at 6 months (Visit 2)	6 months (Visit 2)
Secondary	Percentages of Clinically Stable Patients for Whom the Cardiologist and/or Primary Care Physician Optimizes Treatment Post Referral, Stratified According to Key Baseline Characteristics	For patients who enter the prospective period of the study the post-referral treatment choice of cardiologists and/or primary care physicians was documented; for patients, for whom the cardiologist and/or primary care physician chose to prescribe a novel Heart Failure treatment, the treatment was assessed, if it fulfills the definition of adherence to European Society of Cardiology (ESC) guideline recommendation. The proportion of patients for whom an ESC guideline adherent treatment was de novo prescribed was assessed stratified according to different parameters.	6 months
Secondary	Number of Patients With Different NT-proBNP Level Categories	NT-proBNP levels (pg/ml) was measured at baseline in all consecutive patients who satisfy the inclusion and exclusion criteria. Measurements were performed on-site by means of a handheld device provided for the purposes of the study. NT-proBNP level categories could be 600 -799 pg/ml, 800 - 999 pg/ml, 1000 - 1200 pg/ml, > 1200 pg/ml).	One measurement in all consecutive patients at baseline (Visit 1)
Secondary	Percentages of Clinically Stable Patients	Clinically stable patients in this study were defined as those patients for whom the primary care physician did not see a necessity (based on signs and symptoms of HF) to change the current pharmacological and/or device treatment of HF and who were on stable pharmacological and/or device treatment for HF for at least 3 months prior to inclusion.	Baseline (Visit 1)
Secondary	Number of Patients by Cardiologist Prescription Practice Per Country/Region	The cardiologists' suggestions for pharmacological and/or device therapy for the treatment of clinically stable CHF patients was documented and assessed by means of descriptive statistical measures stratified by country/region 6 months after baseline.	6 months
Secondary	Change of NT-proBNP Levels in Clinically Stable Chronic Heart Failure Patients With and Without Treatment Optimization 10 Months After Baseline	At 10 months after baseline (end of study) NT-proBNP was assessed in clinically stable CHF patients with baseline NT-proBNP levels = 600 pg/ml. Thus, for those patients two NT-proBNP measurements were available: at baseline and 10 months later. The individual change of NT-proBNP between both time points were assessed in accordance to the patients' treatment history during the study, i.e. baseline Heart Failure treatment and therapeutic decision taken 6 months after baseline.	10 months
Secondary	Change in EuroQol Five Dimensions Questionnaire (EQ-5D) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months)	Quality of life (QoL) was assessed by EQ-5D including the dimensions mobility, self-care, usual activity, pain/discomfort, anxiety/depression. A utility index based on UK value sets was built to summarize the information of these five dimensions into a single scale. The utility index can range between -0.281 and 1.0 where a higher number indicates a better health status. In addition, a visual analog scale (VAS) was applied with a possible range between 0 (=worst imaginable health state) and 100 (=best imaginable health state). Scores collected for all patients at baseline (Visit 1) and at Visit 2 and Visit 3 (only patients who entered the prospective period of the study, i.e. clinically stable patients with a NT-proBNP level = 600 pg/ml) were asked to fill out the EuroQol 5D (EQ-5D) quality of life (QoL) questionnaire validated for heart failure (HF).	Baseline (Visit 1), 6 months (Visit 2), 10 months (Visit 3)
Secondary	Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months)	The KCCQ is a self-administered questionnaire. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and quality of life, each with different Likert scale wording, including limitations, frequency, bother, change in condition, understanding, levels of enjoyment and satisfaction. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. A positive change from baseline indicates improvement. Scores were collected for all patients at baseline and Visit 2 and Visit 3 (only patients who had entered the prospective period of the study (clinically stable patients with a NT-proBNP level = 600 pg/ml) were asked to complete Kansas City Cardiomyopathy Questionnaire (KCCQ) validated for Heart Failure.	Baseline (Visit 1), 6 months (Visit 2), 10 months (Visit 3)
Secondary	Number of Patients in Different Living Conditions	Living conditions were collected at Baseline (Visit 1).	Baseline (Visit 1)
Secondary	Number of Patients in Different Employment Status	Employment status was collected at Baseline (Visit 1).	Baseline (Visit 1)
Secondary	Number of Patients With Smoking Status	Smoking status was collected at baseline (visit 1).	Baseline (Visit 1)
Secondary	Number of Patients From Different Geographical Regions	Geographic regions were collected at Baseline (Visit 1).	Baseline (visit 1)
Secondary	Number of Patients With Health Insurance Status	Health insurance status was collected at Baseline (Visit 1).	Baseline (Visit 1)
Secondary	Number of Patients at Different Educational Level	Educational level was collected at Baseline (Visit 1).	Baseline (Visit 1)
Secondary	Number of Patients Per Primary Etiology of Heart Failure	The primary etiology of Heart Failure was collected at Baseline (Visit 1).	Baseline (Visit 1)
Secondary	Number of Patients With Heart Failure (HF)-Related Hospitalizations in the Previous 12 Months Prior to Baseline, and During the Study	HF-related hospitalizations was collected in the previous 12 months prior to baseline at baseline visit, at 6 and 10 months post-baseline.	Baseline (Visit 1), 6 months, 10 months
Secondary	Percentage of Patients With Cardiovascular and Non-cardiovascular Co-morbidities	Cardiovascular and non-cardiovascular co-morbidities were collected at baseline (Visit 1)	Baseline (Visit 1)
Secondary	Mean Dose of Previously Taken and Current Use of Concomitant Medications	Mean Dose of previously taken and current use of concomitant medications was to be collected at Visit 1, 6 months, 10 months post-baseline	Baseline (Visit 1), 6 months, 10 months
Secondary	Number of Heart Failure (HF) Treatment Combinations	The types and number of participants with HF treatment combinations were collected at Baseline (Visit 1).	Baseline (Visit 1)
Secondary	Duration of Treatment With Device Type	The duration of treatment with device type was collected at baseline (Visit 1)	Baseline (Visit 1)
Secondary	Duration of Previously Taken and Currently Use of Most Common Non-Heart Failure Concomitant Compounds	Duration of most common previously taken and current use of most common Non-HF concomitant compounds were collected	Baseline (Visit 1)
Secondary	Number of Patients by Primary Care Physicians' Prescription Practice Per Country/Region	For clinically stable CHF patients, the primary care physicians' prescription of pharmacological and device treatment for HF was to be documented prior to baseline and post cardiologist-referral. At the post-referral visit the degree of implementation of cardiologist-recommendations and the medical decision making (e.g. reasons for non-implementation) were to be documented.	Baseline (Visit 1)