Association of Natriuretic Peptides with Cardiovascular Prognosis in Heart Failure with Preserved Ejection Fraction: Secondary Analysis of the TOPCAT Randomized Clinical Trial

Peder Langeland Myhre, Muthiah Vaduganathan, Brian L. Claggett, Inder S. Anand, Nancy K Sweitzer, James C. Fang, Eileen O'Meara, Sanjiv J. Shah, Akshay S. Desai, Eldrin F. Lewis, Jean Rouleau, Bertram Pitt, Marc A. Pfeffer, Scott D. Solomon

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Importance: Contemporary clinical trials of heart failure with preserved ejection fraction (HFpEF) apply natriuretic peptide (NP) thresholds to identify patients who are more likely to have the disease of interest and to enrich the baseline risk of the enrolled cohort. Objective: To determine whether age, race/ethnicity, obesity, renal function, and atrial fibrillation (AF) affect the levels of NPs in HFpEF and whether the prognostic significance of NPs varies in these clinically important subgroups. Design, Setting, and Participants: This secondary analysis of the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT) evaluated the distribution and prognostic significance of NPs across 6 subgroups comprising 1057 adult patients (60%) in the Americas region of TOPCAT with symptomatic heart failure (HF) and a left ventricular ejection fraction of 45% or more with available NPs at baseline. Exposures: Natriuretic peptides were log-transformed and standardized (expressed per 1 SD, z score) and assessed in 6 subgroups: age (cutoff, 70 years), black race, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared; cutoff, 30 kg/m2), waist circumference (cutoff, 102 cm for men, 88 cm for women), estimated glomerular filtration rate (cutoff, 60 mL/min/1.73 m2), and a history of AF. Main Outcomes and Measures: Time to composite cardiovascular death, hospitalization for HF, or aborted cardiac arrest at mean (SD) 2.4-year (1.5) follow-up. Results: Of 1057 participants, the mean (SD) age was 72 (10) years, 183 (17.3%) were black, the mean (SD) BMI was 33.4 (8.6) kg/m2, the mean (SD) estimated glomerular filtration rate was 64.6 (21.8) mL/min/1.73 m2, and 472 (45%) had a history of AF. Median B-type NP (n = 698) and N-terminal pro-B-type NP concentrations (n = 359) were 257 (interquartile range, 149-443) ng/L and 959 (interquartile range, 554-2015) ng/L, respectively. Natriuretic peptide concentrations varied by up to 0.5 SD within the 6 subgroups, being higher in older patients with nonblack race, a lower BMI, a lower waist circumference, a lower estimated glomerular filtration rate, and a history of AF. Elevated NP levels (per 1-SD increase) were independently associated with an increased risk of the primary outcome (adjusted hazard ratio, 1.36; 95% CI, 1.22-1.54; P <.001) consistently across all investigated subgroups (interaction P >.05). In TOPCAT Americas (n = 1767), 791 (45%) were enrolled based on elevated NP levels as the qualifying criterion (as opposed to a history of HF hospitalization). This proportion was 31% (93 of 302), 34% (258 of 760), and 39% (443 of 1144) for black race, younger than 70 years, and a BMI of 30 kg/m2 or greater, respectively. Conclusions and Relevance: Natriuretic peptides remain important biomarkers of prognosis in HFpEF, even in subgroups who tend to have lower NP levels. A single, absolute NP threshold for inclusion in contemporary HFpEF trials may lead to an underrepresentation of certain demographic and clinical subgroups.

Original languageEnglish (US)
JournalJAMA Cardiology
DOIs
StateAccepted/In press - Jan 1 2018

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Natriuretic Peptides
Randomized Controlled Trials
Heart Failure
Atrial Fibrillation
Glomerular Filtration Rate
Brain Natriuretic Peptide
Waist Circumference
Hospitalization
Mineralocorticoid Receptor Antagonists
Heart Arrest
Stroke Volume
Body Mass Index
Obesity
Biomarkers
Demography
Outcome Assessment (Health Care)
Clinical Trials
Kidney
Weights and Measures

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Association of Natriuretic Peptides with Cardiovascular Prognosis in Heart Failure with Preserved Ejection Fraction : Secondary Analysis of the TOPCAT Randomized Clinical Trial. / Myhre, Peder Langeland; Vaduganathan, Muthiah; Claggett, Brian L.; Anand, Inder S.; Sweitzer, Nancy K; Fang, James C.; O'Meara, Eileen; Shah, Sanjiv J.; Desai, Akshay S.; Lewis, Eldrin F.; Rouleau, Jean; Pitt, Bertram; Pfeffer, Marc A.; Solomon, Scott D.

In: JAMA Cardiology, 01.01.2018.

Research output: Contribution to journalArticle

Myhre, PL, Vaduganathan, M, Claggett, BL, Anand, IS, Sweitzer, NK, Fang, JC, O'Meara, E, Shah, SJ, Desai, AS, Lewis, EF, Rouleau, J, Pitt, B, Pfeffer, MA & Solomon, SD 2018, 'Association of Natriuretic Peptides with Cardiovascular Prognosis in Heart Failure with Preserved Ejection Fraction: Secondary Analysis of the TOPCAT Randomized Clinical Trial', JAMA Cardiology. https://doi.org/10.1001/jamacardio.2018.2568
Myhre, Peder Langeland ; Vaduganathan, Muthiah ; Claggett, Brian L. ; Anand, Inder S. ; Sweitzer, Nancy K ; Fang, James C. ; O'Meara, Eileen ; Shah, Sanjiv J. ; Desai, Akshay S. ; Lewis, Eldrin F. ; Rouleau, Jean ; Pitt, Bertram ; Pfeffer, Marc A. ; Solomon, Scott D. / Association of Natriuretic Peptides with Cardiovascular Prognosis in Heart Failure with Preserved Ejection Fraction : Secondary Analysis of the TOPCAT Randomized Clinical Trial. In: JAMA Cardiology. 2018.
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abstract = "Importance: Contemporary clinical trials of heart failure with preserved ejection fraction (HFpEF) apply natriuretic peptide (NP) thresholds to identify patients who are more likely to have the disease of interest and to enrich the baseline risk of the enrolled cohort. Objective: To determine whether age, race/ethnicity, obesity, renal function, and atrial fibrillation (AF) affect the levels of NPs in HFpEF and whether the prognostic significance of NPs varies in these clinically important subgroups. Design, Setting, and Participants: This secondary analysis of the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT) evaluated the distribution and prognostic significance of NPs across 6 subgroups comprising 1057 adult patients (60{\%}) in the Americas region of TOPCAT with symptomatic heart failure (HF) and a left ventricular ejection fraction of 45{\%} or more with available NPs at baseline. Exposures: Natriuretic peptides were log-transformed and standardized (expressed per 1 SD, z score) and assessed in 6 subgroups: age (cutoff, 70 years), black race, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared; cutoff, 30 kg/m2), waist circumference (cutoff, 102 cm for men, 88 cm for women), estimated glomerular filtration rate (cutoff, 60 mL/min/1.73 m2), and a history of AF. Main Outcomes and Measures: Time to composite cardiovascular death, hospitalization for HF, or aborted cardiac arrest at mean (SD) 2.4-year (1.5) follow-up. Results: Of 1057 participants, the mean (SD) age was 72 (10) years, 183 (17.3{\%}) were black, the mean (SD) BMI was 33.4 (8.6) kg/m2, the mean (SD) estimated glomerular filtration rate was 64.6 (21.8) mL/min/1.73 m2, and 472 (45{\%}) had a history of AF. Median B-type NP (n = 698) and N-terminal pro-B-type NP concentrations (n = 359) were 257 (interquartile range, 149-443) ng/L and 959 (interquartile range, 554-2015) ng/L, respectively. Natriuretic peptide concentrations varied by up to 0.5 SD within the 6 subgroups, being higher in older patients with nonblack race, a lower BMI, a lower waist circumference, a lower estimated glomerular filtration rate, and a history of AF. Elevated NP levels (per 1-SD increase) were independently associated with an increased risk of the primary outcome (adjusted hazard ratio, 1.36; 95{\%} CI, 1.22-1.54; P <.001) consistently across all investigated subgroups (interaction P >.05). In TOPCAT Americas (n = 1767), 791 (45{\%}) were enrolled based on elevated NP levels as the qualifying criterion (as opposed to a history of HF hospitalization). This proportion was 31{\%} (93 of 302), 34{\%} (258 of 760), and 39{\%} (443 of 1144) for black race, younger than 70 years, and a BMI of 30 kg/m2 or greater, respectively. Conclusions and Relevance: Natriuretic peptides remain important biomarkers of prognosis in HFpEF, even in subgroups who tend to have lower NP levels. A single, absolute NP threshold for inclusion in contemporary HFpEF trials may lead to an underrepresentation of certain demographic and clinical subgroups.",
author = "Myhre, {Peder Langeland} and Muthiah Vaduganathan and Claggett, {Brian L.} and Anand, {Inder S.} and Sweitzer, {Nancy K} and Fang, {James C.} and Eileen O'Meara and Shah, {Sanjiv J.} and Desai, {Akshay S.} and Lewis, {Eldrin F.} and Jean Rouleau and Bertram Pitt and Pfeffer, {Marc A.} and Solomon, {Scott D.}",
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TY - JOUR

T1 - Association of Natriuretic Peptides with Cardiovascular Prognosis in Heart Failure with Preserved Ejection Fraction

T2 - Secondary Analysis of the TOPCAT Randomized Clinical Trial

AU - Myhre, Peder Langeland

AU - Vaduganathan, Muthiah

AU - Claggett, Brian L.

AU - Anand, Inder S.

AU - Sweitzer, Nancy K

AU - Fang, James C.

AU - O'Meara, Eileen

AU - Shah, Sanjiv J.

AU - Desai, Akshay S.

AU - Lewis, Eldrin F.

AU - Rouleau, Jean

AU - Pitt, Bertram

AU - Pfeffer, Marc A.

AU - Solomon, Scott D.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Importance: Contemporary clinical trials of heart failure with preserved ejection fraction (HFpEF) apply natriuretic peptide (NP) thresholds to identify patients who are more likely to have the disease of interest and to enrich the baseline risk of the enrolled cohort. Objective: To determine whether age, race/ethnicity, obesity, renal function, and atrial fibrillation (AF) affect the levels of NPs in HFpEF and whether the prognostic significance of NPs varies in these clinically important subgroups. Design, Setting, and Participants: This secondary analysis of the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT) evaluated the distribution and prognostic significance of NPs across 6 subgroups comprising 1057 adult patients (60%) in the Americas region of TOPCAT with symptomatic heart failure (HF) and a left ventricular ejection fraction of 45% or more with available NPs at baseline. Exposures: Natriuretic peptides were log-transformed and standardized (expressed per 1 SD, z score) and assessed in 6 subgroups: age (cutoff, 70 years), black race, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared; cutoff, 30 kg/m2), waist circumference (cutoff, 102 cm for men, 88 cm for women), estimated glomerular filtration rate (cutoff, 60 mL/min/1.73 m2), and a history of AF. Main Outcomes and Measures: Time to composite cardiovascular death, hospitalization for HF, or aborted cardiac arrest at mean (SD) 2.4-year (1.5) follow-up. Results: Of 1057 participants, the mean (SD) age was 72 (10) years, 183 (17.3%) were black, the mean (SD) BMI was 33.4 (8.6) kg/m2, the mean (SD) estimated glomerular filtration rate was 64.6 (21.8) mL/min/1.73 m2, and 472 (45%) had a history of AF. Median B-type NP (n = 698) and N-terminal pro-B-type NP concentrations (n = 359) were 257 (interquartile range, 149-443) ng/L and 959 (interquartile range, 554-2015) ng/L, respectively. Natriuretic peptide concentrations varied by up to 0.5 SD within the 6 subgroups, being higher in older patients with nonblack race, a lower BMI, a lower waist circumference, a lower estimated glomerular filtration rate, and a history of AF. Elevated NP levels (per 1-SD increase) were independently associated with an increased risk of the primary outcome (adjusted hazard ratio, 1.36; 95% CI, 1.22-1.54; P <.001) consistently across all investigated subgroups (interaction P >.05). In TOPCAT Americas (n = 1767), 791 (45%) were enrolled based on elevated NP levels as the qualifying criterion (as opposed to a history of HF hospitalization). This proportion was 31% (93 of 302), 34% (258 of 760), and 39% (443 of 1144) for black race, younger than 70 years, and a BMI of 30 kg/m2 or greater, respectively. Conclusions and Relevance: Natriuretic peptides remain important biomarkers of prognosis in HFpEF, even in subgroups who tend to have lower NP levels. A single, absolute NP threshold for inclusion in contemporary HFpEF trials may lead to an underrepresentation of certain demographic and clinical subgroups.

AB - Importance: Contemporary clinical trials of heart failure with preserved ejection fraction (HFpEF) apply natriuretic peptide (NP) thresholds to identify patients who are more likely to have the disease of interest and to enrich the baseline risk of the enrolled cohort. Objective: To determine whether age, race/ethnicity, obesity, renal function, and atrial fibrillation (AF) affect the levels of NPs in HFpEF and whether the prognostic significance of NPs varies in these clinically important subgroups. Design, Setting, and Participants: This secondary analysis of the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT) evaluated the distribution and prognostic significance of NPs across 6 subgroups comprising 1057 adult patients (60%) in the Americas region of TOPCAT with symptomatic heart failure (HF) and a left ventricular ejection fraction of 45% or more with available NPs at baseline. Exposures: Natriuretic peptides were log-transformed and standardized (expressed per 1 SD, z score) and assessed in 6 subgroups: age (cutoff, 70 years), black race, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared; cutoff, 30 kg/m2), waist circumference (cutoff, 102 cm for men, 88 cm for women), estimated glomerular filtration rate (cutoff, 60 mL/min/1.73 m2), and a history of AF. Main Outcomes and Measures: Time to composite cardiovascular death, hospitalization for HF, or aborted cardiac arrest at mean (SD) 2.4-year (1.5) follow-up. Results: Of 1057 participants, the mean (SD) age was 72 (10) years, 183 (17.3%) were black, the mean (SD) BMI was 33.4 (8.6) kg/m2, the mean (SD) estimated glomerular filtration rate was 64.6 (21.8) mL/min/1.73 m2, and 472 (45%) had a history of AF. Median B-type NP (n = 698) and N-terminal pro-B-type NP concentrations (n = 359) were 257 (interquartile range, 149-443) ng/L and 959 (interquartile range, 554-2015) ng/L, respectively. Natriuretic peptide concentrations varied by up to 0.5 SD within the 6 subgroups, being higher in older patients with nonblack race, a lower BMI, a lower waist circumference, a lower estimated glomerular filtration rate, and a history of AF. Elevated NP levels (per 1-SD increase) were independently associated with an increased risk of the primary outcome (adjusted hazard ratio, 1.36; 95% CI, 1.22-1.54; P <.001) consistently across all investigated subgroups (interaction P >.05). In TOPCAT Americas (n = 1767), 791 (45%) were enrolled based on elevated NP levels as the qualifying criterion (as opposed to a history of HF hospitalization). This proportion was 31% (93 of 302), 34% (258 of 760), and 39% (443 of 1144) for black race, younger than 70 years, and a BMI of 30 kg/m2 or greater, respectively. Conclusions and Relevance: Natriuretic peptides remain important biomarkers of prognosis in HFpEF, even in subgroups who tend to have lower NP levels. A single, absolute NP threshold for inclusion in contemporary HFpEF trials may lead to an underrepresentation of certain demographic and clinical subgroups.

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