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Heart failure: biomarker effect and influence on quality of life
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background and aims: Heart failure (HF) is a life threatening condition and optimal handling is necessary to reduce risk of therapy failure. The aims of this thesis were: (Paper I) to examine whether BNP (B-type natriuretic peptide)-guided HF treatment improves morbidity and mortality when compared with HF therapy implemented by a treating physician at sites experienced in managing patients with HF according to guidelines; (Paper II) to investigate how to define a responder regarding optimal cut-off level of BNP to predict death, need for hospitalisation, and worsening HF and to determine the optimal time to apply the chosen cut-off value; (Paper III) to evaluate how Health-Related Quality of Life (HR-QoL) is influenced by natriuretic peptide guiding and to study how HR-QoL is affected in responders compared to non-responders; (Paper IV) to evaluate the impact of patient age on clinical outcomes, and to evaluate the impact of duration of the HF disease on outcomes and the impact of age and HF duration on BNP concentration.

Methods: A randomized, parallel group, multi-centre study was undertaken on 279 patients with HF and who had experienced an episode of worsening HF with increased BNP concentration. The control group (n=132) was treated according to HF guidelines and in the BNP-guided group (n=147) the HF treatment algorithm goal was to reduce BNP concentration to < 150 ng/L in patients < 75 years and <300 ng/L in patients > 75 years (Paper I), and to define the optimal percentage decrease in BNP and at what point during the follow-up to apply the definition (Paper II). To compare the BNP-guided group with the conventional HF treated group (Paper I), and responders and non-responders (Paper II) regarding HR-QoL measured with Short Form 36 (SF-36) at study start and at study end (Paper III) and to evaluate if age or HF duration influenced the HF outcomes and the influence of BNP on age and HF duration (Paper IV).

Results: The primary outcome (mortality, hospitalisation and worsening HF) was not improved by BNP-guided HF treatment compared to conventional HF treatment or in any of the secondary outcome variables (Paper I). Applying a BNP decrease of at least 40 percent in week 16 (compared to study start) and/or a BNP<300 ng/L demonstrated the best risk reduction for cardiovascular mortality, by 78 percent and 89 percent respectively for HF mortality (Paper II). The HR-QoL improved in four domains in the BNP-guided group and in the control group in six of eight domains; however there were no significant differences between the groups (Paper III). For responders the within group analysis showed improvement in four domains compared to the non-responders that improved in one domain; however there were no significant differences between the two groups. There were improvements in HR-QoL in all four groups (Paper III). Age did not influence outcome but HF duration did. HF duration was divided into three groups: HF duration less than 1 year (group 1), 1-5 years (group 2) and >5 years (group 3). A 1.65-fold increased risk could be demonstrated in those with HF duration of more than five years compared to patients with short HF duration. The BNP concentration was increased with increased age, and there was a better response regarding BNP decrease in NP-guiding in patients with short HF duration, independent of age (Paper IV).

Conclusions: There were no significant differences between BNP-guided HF treatment group and the group with conventional HF treatment as regards mortality, hospitalisation or HR-QoL. The responders to HF treatment showed a significantly better outcome in mortality and hospitalisation compared to non-responders but no significant differences in HR-QoL. The duration of HF might be an important factor to consider in HF treatment by BNP-guiding in the future.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. , 123 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1499
Keyword [en]
Heart failure, Biomarker, B-type natriuretic peptide, Heart failure treatment, B-type Natriuretic Peptide guided heart failure treatment, Responders, Health-related quality of life, Heart failure duration, Outcomes
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:liu:diva-124560DOI: 10.3384/diss.diva-124560ISBN: 978-91-7685-869-1 (print)OAI: oai:DiVA.org:liu-124560DiVA: diva2:900081
Public defence
2016-03-04, Belladonna, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Funder
Swedish Heart Lung Foundation
Available from: 2016-02-03 Created: 2016-02-03 Last updated: 2016-02-09Bibliographically approved
List of papers
1. Brain natriuretic peptide-guided treatment does not improve morbidity and mortality in extensively treated patients with chronic heart failure: responders to treatment have a significantly better outcome
Open this publication in new window or tab >>Brain natriuretic peptide-guided treatment does not improve morbidity and mortality in extensively treated patients with chronic heart failure: responders to treatment have a significantly better outcome
2011 (English)In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 13, no 10, 1096-1103 p.Article in journal (Refereed) Published
Abstract [en]

Aim To determine whether brain natriuretic peptide (BNP)-guided heart failure (HF) treatment improves morbidity and/or mortality when compared with conventional treatment. less thanbrgreater than less thanbrgreater thanMethods and results UPSTEP was an investigator-initiated, randomized, parallel group, multicentre study with a PROBE design. Symptomatic patients with worsening HF, New York Heart Association class II-IV, ejection fraction andlt;40% and elevated BNP levels, were included. All patients (n = 279) were treated according to recommended guidelines and randomized to BNP-guided (BNP) or to conventional (CTR) HF treatment. The goal was to reduce BNP levels to andlt;150 ng/L in younger patients and andlt;300 ng/L in elderly patients, respectively. The primary outcome was a composite of death due to any cause, need for hospitalization and worsening HF. The study groups were well matched, including for BNP concentration at entry (mean: 808 vs. 899 ng/L; P = 0.34). There were no significant differences between the groups regarding either the primary outcome (P = 0.18) or any of the secondary endpoints. There were no differences for the pre-specified analyses; days out of hospital, and younger vs. elderly. A subgroup analysis comparing treatment responders (andgt;30% decrease in baseline BNP value) vs. non-responders found improved survival among responders (P andlt; 0.0001 for the primary outcome), and all of the secondary endpoints were also improved. less thanbrgreater than less thanbrgreater thanConclusions Morbidity and mortality were not improved by HF treatment guided by BNP levels. However, BNP responders had a significantly better clinical outcome than non-responders. Future research is needed to elucidate the responsible pathophysiological mechanisms in this sub-population.

Place, publisher, year, edition, pages
Oxford University Press, 2011
Keyword
PROBE design, Systolic heart failure, Natriuretic peptides, BNP-guided treatment
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71379 (URN)10.1093/eurjhf/hfr078 (DOI)000295169600009 ()
Note

Funding Agencies|Swedish Heart-Lung Foundation||Regional Research Foundation in South-eastern Sweden||Regional Research Foundation in Northern Sweden||Biosite International||Infiniti Medical AB||

Available from: 2011-10-14 Created: 2011-10-14 Last updated: 2017-12-08
2. Responder to BNP-guided treatment in heart failure. The process of defining a responder.
Open this publication in new window or tab >>Responder to BNP-guided treatment in heart failure. The process of defining a responder.
2015 (English)In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 49, no 6, 316-324 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: B-type natriuretic peptide (BNP) levels predict prognosis and outcome in heart failure (HF) patients. To evaluate the optimal cut-off level of BNP to predict death, need for hospitalization, and worsening HF, and also to determine the optimal time to apply the chosen cut-off value.

DESIGN: In a sub-study from the Use of PeptideS in Tailoring hEart failure Project or UPSTEP study where tailoring treatment of HF by BNP level was evaluated, we assessed the change in percentage between levels of BNP at study start versus a specific week (2, 6, 10, 16, 24, 36, or 48) during the follow-up period.

RESULTS: The optimum cut-off percentage levels were obtained using a Cox proportional regression analysis of death, hospitalization, and worsening HF. A decrease in BNP by less than 40% in week 16 compared with study start and/or a BNP > 300 ng/L presented the highest hazard ratio (HR) for a non-responder to reach a combined endpoint (HR: 2.43; 95% confidence interval or CI: 1.61-3.65; p < 0.00003). This definition gave a 78% risk reduction of cardiovascular (CV) mortality (p > 0.0005) and an 89% risk reduction of HF mortality (p > 0.004), and reduced risk of CV and HF hospitalization for the responders.

CONCLUSIONS: Patients with a decrease in BNP of more than 40% compared with that at study start and/or a BNP level below 300 ng/L at week 16 had a significantly reduced risk of CV and HF mortality and hospitalization.

Keyword
BNP; heart failure; natriuretic peptides; responder; treatment
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-123450 (URN)10.3109/14017431.2015.1070961 (DOI)000369893500003 ()26153427 (PubMedID)
Note

Funding agencies: Linnaeus University, Sweden

Available from: 2015-12-17 Created: 2015-12-17 Last updated: 2017-12-01Bibliographically approved
3. Can BNP-guided therapy improve health-related quality of life, and do responders to BNP-guided heart failure treatment have improved health-related quality of life? Results from the UPSTEP study.
Open this publication in new window or tab >>Can BNP-guided therapy improve health-related quality of life, and do responders to BNP-guided heart failure treatment have improved health-related quality of life? Results from the UPSTEP study.
Show others...
2016 (English)In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 16Article in journal (Refereed) Published
Abstract [en]

Background: To investigate whether B-type natriuretic peptide (NP)-guided treatment of heart failure (HF) patients improved their health related quality of life (Hr-QoL) compared to routine HF treatment, and whether changes in Hr-QoL differed depending on whether the patient was a responder to NP-guided therapy or not.

Methods: A secondary analysis of the UPSTEP-study, a Scandinavian multicentre study using a prospective, randomized, open, blinded evaluation design on patients with HF with New York Heart Association (NYHA) class II-IV. NP-guiding was aimed to reduce BNP <150 ng/L if<75 years or BNP<300 ng/L if>75 years. A responder was defined as a patient with a BNP<300 ng/L and/or a decrease in BNP of at least 40 % in week 16 compared to study start. Short form-36 (SF-36) was used to measure Hr-QoL. At the study start, 258 patients presented evaluable SF-36 questionnaires, 131 in the BNP group and 127 in the control group. At the study end 100 patients in the NP-guided group and 98 in the control group, presenting data from both the study start and the study end.

Results: There were no significant differences in Hr-QoL between NP-guided HF treatment and control group; however significant improvements could be seen in four of the eight domains in the NP-guided group, whereas in the control group improvements could be seen in six of the domains.

Among the responders improvements could be noted in four domains whereas in the non-responders improvements could be seen in only one domain evaluating within group changes.

Conclusions: Improved Hr-QoL could be demonstrated in several of the domains in both the NP-guided and the control group. In the responder group within group analyses showed more increased Hr-QoL compared to the non-responder group. However, all groups demonstrated increase in Hr-QoL.

Place, publisher, year, edition, pages
BioMed Central, 2016
Keyword
Heart failure, treatment guided by natriuretic peptides, Health related quality of life, responders, BNP, SF-36
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-124558 (URN)10.1186/s12872-016-0221-7 (DOI)000370472800001 ()
Note

Vid tiden för disputationen förelåg publikationen endast som manuskript

Funding agencies:  Swedish Heart-lung foundation [20060596]; Regional Research Foundation in south-eastern Sweden [FORSS-3963]; Regional Research Foundation in northern Sweden; Biosite international; Infiniti Medical AB

Available from: 2016-02-03 Created: 2016-02-03 Last updated: 2017-11-30Bibliographically approved
4. Time since heart failure diagnosis influences outcomes more than age when handling heart failure patients: Results from the UPSTEP study
Open this publication in new window or tab >>Time since heart failure diagnosis influences outcomes more than age when handling heart failure patients: Results from the UPSTEP study
Show others...
2016 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Heart failure (HF) is a life-threatening condition and optimal handling is necessary to reduce risk of therapy failure.

Objectives: The aims of this study were (I) to evaluate the impact of patient age on clinical outcomes, (II) to evaluate the impact of duration of the HF disease on outcomes, and (III) to evaluate the impact of age and HF duration on B-type Natriuretic Peptide (BNP) concentration.

Methods and Results: With data from the UPSTEP (Use of PeptideS in Tailoring hEart failure Project) study we retrospectively evaluated how age and HF duration affected HF outcome. HF duration was divided into <1 year (group 1), 1-5 years (group 2) and >5 years (group 3). The multivariate Cox proportional hazard regression analysis showed that HF duration influenced outcome more than age, even when adjusted for comorbidities(<1 year versus >5 years: HR 1.65; 95 % CI 1.28-2.14; p <0.0002) on HF mortality and hospitalizations. The influence of age on BNP showed increased BNP as age increased. However, there was a significant effect on BNP concentration comparing HF duration of < one year to HF duration >five years even when adjusted for age.

Conclusions: Patients with longer HF duration had significantly worse outcome compared to those with short duration, even when adjusted for patient age and comorbidities. Age itself did not influence outcome in this evaluation. Age had impact on BNP concentration; however BNP concentration increased as HF duration increased even when adjusted for age.

Keyword
Heart failure, B-type natriuretic peptides, age, heart failure duration
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-124559 (URN)
Available from: 2016-02-03 Created: 2016-02-03 Last updated: 2016-02-03Bibliographically approved

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