Pulse Pressure in Heart Failure with Mildly Reduced or Preserved Ejection Fraction: A Pooled Participant-Level Analysis of 4 Large-Scale Trials
Abstract Body (Do not enter title and authors here): Background Pulse pressure (PP), a marker of aortic stiffness, is associated with risk for mortality and cardiovascular (CV) events, but these associations have not been extensively explored in patients with heart failure (HF). We examined the association between PP and CV outcomes in a pooled dataset of 4 large, well-characterized cohorts of patients with HF with moderately reduced (mrEF) or preserved EF (pEF).
Methods I-PRESERVE, TOPCAT, PARAGON-HF and DELIVER were global, multicenter, randomized clinical trials testing irbesartan, spironolactone, sacubitril/valsartan and dapagliflozin respectively, against either a placebo or an active control (valsartan in PARAGON-HF), in patients with HF and a LVEF >40% (in DELIVER) or ≥45% (in the other trials). Predictors of higher PP were identified using forward stepwise regression analysis. The relationship between baseline continuous PP and the incidence rates (IR) of first HF hospitalization (HFH) or CV death was analyzed with restricted cubic splines. To assess the prognostic significance of incorporating systolic blood pressure (SBP) along with PP, we categorized patients into 4 groups based on median values of PP and SBP.
Results A total of 18,627 patients (age 71±9 years, 49% men, PP 55±14 mmHg, SBP 131±15 mmHg) were included. Over a median follow-up of 2.9 years, 3,852 patients experienced a first HFH or CV death event (7.4 events per 100py). Predictors of higher PP values included higher SBP, older age, female sex, Asian race, higher EF, use of diuretics, higher N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, and diabetes. Conversely, factors associated with lower PP included atrial fibrillation, higher heart rate, worse New York Heart Association (NYHA) Functional Class, use of beta-blockers, and higher estimated glomerular filtration rate. After adjusting for predictors of PP and other relevant variables, higher PP was associated with a higher risk for HFH or CV death. This relationship was nonlinear (p<0.001), with risk increasing markedly at higher PP values (Figure 1). After multivariable adjustment, higher PP was associated with higher CV risk regardless of baseline SBP, compared to lower PP and lower SBP (Figure 2).
Conclusions Our analysis of a pooled dataset from 4 clinical trials including patients with HFmrEF or pEF suggests that PP was an independent predictor of CV events in this population, regardless of baseline SBP.
Lu, Henri
( Brigham and Women's Hospital
, Boston
, Massachusetts
, United States
)
Pfeffer, Marc
( Brigham and Women's Hospital
, Boston
, Massachusetts
, United States
)
Pitt, Bertram
( University of Michigan School
, Ann Arbor
, Michigan
, United States
)
Zannad, Faiez
( INSERM-CIC
, Vandoeuvre Les Nancy
, France
)
Zile, Michael
( MEDICAL UNIV OF SOUTH CAROLINA
, Charleston
, South Carolina
, United States
)
Mcmurray, John
( BHF CARDIOVASCULAR RESEARCH CENTRE
, Glasgow
, United Kingdom
)
Solomon, Scott
( Brigham and Women's Hospital
, Boston
, Massachusetts
, United States
)
Desai, Akshay
( Brigham and Women's Hospital
, Boston
, Massachusetts
, United States
)
Kondo, Toru
( Nagoya University
, Nagoya
, Japan
)
Claggett, Brian
( Brigham and Women's Hospital
, Boston
, Massachusetts
, United States
)
Vaduganathan, Muthiah
( Brigham and Women's Hospital
, Boston
, Massachusetts
, United States
)
Neuen, Brendon
( George Institute for Global Health
, Newtown
, New South Wales
, Australia
)
Beldhuis, Iris
( UMCG
, Groningen
, Netherlands
)
Jhund, Pardeep
( BHF CARDIOVASCULAR RESEARCH CENTRE
, Glasgow
, United Kingdom
)
Mc Causland, Finnian
( Brigham and Women's Hospital
, Boston
, Massachusetts
, United States
)
Anand, Inder
( VA SAN DIEGO HEATHCARE SYSTEM
, La Jolla
, California
, United States
)
Author Disclosures:
Henri Lu:DO have relevant financial relationships
;
Other (please indicate in the box next to the company name):Gottfried und Julia Bangerter-Rhyner Foundation (fellowship funding):Active (exists now)
; Other (please indicate in the box next to the company name):Société Académique Vaudoise (fellowship funding):Active (exists now)
; Other (please indicate in the box next to the company name):SICPA Foundation (fellowship funding):Active (exists now)
| Marc Pfeffer:DO have relevant financial relationships
;
Consultant:Alexion, Alnylam, Apnimed, AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, DalCor, Intellia, Novartis, and Novo Nordisk. :Active (exists now)
; Individual Stocks/Stock Options:Dal-Cor:Active (exists now)
; Researcher:Lexicon, Novartis:Past (completed)
| Bertram Pitt:No Answer
| Faiez Zannad:No Answer
| Michael Zile:DO NOT have relevant financial relationships
| John McMurray:DO have relevant financial relationships
;
Research Funding (PI or named investigator):British Heart Foundation, National Institute for Health – National Heart Lung and Blood Institute (NIH-NHLBI), Boehringer Ingelheim, SQ Innovations, Catalyze Group. - Payment to Glasgow University:Active (exists now)
; Other (please indicate in the box next to the company name):KBP Biosciences - My employer, Glasgow University, has been paid by KBP Biosciences for my time spent scientific advisor to company to help guide clinical development in cardio-renal disease, inflammation & infection.:Past (completed)
; Consultant:WIRB-Copernicus Group Clinical Inc. - Data Safety Monitoring Board:Active (exists now)
; Other (please indicate in the box next to the company name):Bayer - My employer, Glasgow University, has been paid by Bayer for my time spent as Steering Committee member for the PANACHE trial using neladenoson bialanate and for the FINEARTS trial with finerenone. These payments were made through a Consultancy with Glasgow University and I have not received personal payments in relation to these trials/drugs.:Active (exists now)
; Other (please indicate in the box next to the company name):Glaxo Smith Kline - My employer, Glasgow University, has been paid by GSK for my time spent as Co-principal investigator and Steering Committee member, respectively, for the Harmony-Outcomes trial (albiglutide) and two trials, ASCEND-D and ASCEND-ND, using daprodustat, and meetings related to these trials. GSK has also paid my travel and accommodation for some of these meetings. These payments were made through a Consultancy with Glasgow University and I have not received personal payments in relation to these trials/drugs.:Active (exists now)
; Other (please indicate in the box next to the company name):Novartis - My employer, Glasgow University, has been paid by Novartis for my time spent as Executive Committee member and then co-principal investigator of ATMOSPHERE, co-principal investigator of the PARADIGM-HF and PARAGON-HF trials and Executive/Steering Committee member for PARADISE-MI, PERSPECTIVE and PARACHUTE-HF trials (with sacubitril/valsartan) and meetings/presentations related to these trials and aliskiren and sacubitril/valsartan. Novartis has also paid my travel and accommodation for some of these meetings. These payments were made through a Consultancy with Glasgow University and I have not received personal payments from Novartis in relation to these trials/drugs.:Active (exists now)
; Other (please indicate in the box next to the company name):Cardurion - My employer, Glasgow University, has been paid by Cardurion for my participation in a company advisory board about development of a PDE 9 inhibitor in heart failure.:Active (exists now)
; Consultant:Global Clinical Trial Partners Ltd. - Director:Active (exists now)
; Consultant:Alynylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, BMS, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, River 2 Renal Corp.:Active (exists now)
; Other (please indicate in the box next to the company name):Theracos - My employer, Glasgow University, has been paid by Theracos for my time spent as Principal investigator for the BEST trial and meetings related to this trial. Theracos has also paid my travel and accommodation for some of these meetings. These payments were made through a Consultancy with Glasgow University and I have not received personal payments in relation to this trial/this drug.:Past (completed)
; Other (please indicate in the box next to the company name):Amgen - My employer, Glasgow University, has been paid by Amgen for my time spent as Steering Committee member for the ATOMIC-HF, COSMIC-HF and GALACTIC-HF trials and meetings and other activities related to these trials. Amgen has also paid my travel and accommodation for some of these meetings/activities. These payments were made through a Consultancy with Glasgow University and I have not received personal payments in relation to these trials/this drug.:Active (exists now)
; Other (please indicate in the box next to the company name):Cytokinetics - My employer, Glasgow University, has been paid by Cytokinetics for my time spent as Steering Committee member for the ATOMIC-HF, COSMIC-HF and GALACTIC-HF trials and meetings and other activities related to these trials. Cytokinetics has also paid my travel and accommodation for some of these meetings/activities. These payments were made through a Consultancy with Glasgow University and I have not received personal payments in relation to these trials/this drug.:Active (exists now)
; Speaker:Abbott, Alkem Metabolics, Astra Zeneca, Blue Ocean Scientific Solutions Ltd., Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd., Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals Ltd., Lupin Pharmaceuticals, Medscape/Heart.Org., ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, Translational Medicine Academy - personal lecture fees:Active (exists now)
; Other (please indicate in the box next to the company name):AstraZeneca - My employer, Glasgow University, has been paid by AstraZeneca (who market dapagliflozin) for my time spent as Principal Investigator of DAPA-HF and Co-principal Investigator of DELIVER and DETERMINE (trials using dapagliflozin) in heart failure and meetings and other activities related to these trials. AstraZeneca has also paid my travel and accommodation for these meetings. These payments were made through a Consultancy with Glasgow University and I have not received personal payments in relation to this trial/this drug.:Active (exists now)
| Scott Solomon:DO have relevant financial relationships
;
Research Funding (PI or named investigator):Alexion, Alnylam, Applied Therapeutics, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos/BridgeBio, Gossamer, GSK, Ionis, Lilly,NIH/NHLBI, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Tenaya, Theracos, US2.AI:Active (exists now)
; Consultant:Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, BMS, Cardior, Cardurion, Corvia, Cytokinetics, GSK, Intellia, Lilly, Novartis, Roche, Theracos, Quantum Genomics, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, Valo:Active (exists now)
| Akshay Desai:DO have relevant financial relationships
;
Research Funding (PI or named investigator):Abbott:Active (exists now)
; Individual Stocks/Stock Options:DTX plus:Past (completed)
; Consultant:Veristat, Zydus:Past (completed)
; Consultant:Medpace, Porter Health, Regeneron, River2Renal, Roche, Verily:Active (exists now)
; Consultant:Merck, Medtronic, Parexel, scPharmaceuticals:Past (completed)
; Consultant:Bayer, Biofourmis, Novartis:Active (exists now)
; Consultant:Avidity, Axon Therapeutics, Boston Scientific, GlaxoSmithKline:Past (completed)
; Consultant:Abbott, Alnylam, AstraZeneca:Active (exists now)
; Research Funding (PI or named investigator):Pfizer:Active (exists now)
; Research Funding (PI or named investigator):Novartis:Active (exists now)
; Research Funding (PI or named investigator):Bayer:Active (exists now)
; Research Funding (PI or named investigator):AstraZeneca:Active (exists now)
; Research Funding (PI or named investigator):Alnylam:Active (exists now)
| Toru Kondo:DO have relevant financial relationships
;
Advisor:Astrazeneca:Active (exists now)
; Speaker:Novartis Pharma K.K:Active (exists now)
; Speaker:Kyowa Kirin Co.,Ltd.:Active (exists now)
; Speaker:Kowa Company, Ltd:Active (exists now)
; Speaker:Ono Pharmaceutical Co., Ltd:Active (exists now)
; Speaker:Boehringer Ingelheim:Active (exists now)
; Speaker:Abbott Japan LLC:Active (exists now)
| Brian Claggett:DO have relevant financial relationships
;
Consultant:Cardior:Active (exists now)
; Consultant:Eli Lilly:Active (exists now)
; Consultant:CVRx:Past (completed)
; Consultant:Intellia:Active (exists now)
; Consultant:Cytokinetics:Past (completed)
; Consultant:Cardurion:Active (exists now)
| Muthiah Vaduganathan:DO have relevant financial relationships
;
Researcher:received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health, and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics:Active (exists now)
| Brendon Neuen:DO have relevant financial relationships
;
Consultant:AstraZeneca:Active (exists now)
; Research Funding (PI or named investigator):Menarini:Expected (by end of conference)
; Consultant:Travere Therapeutics:Active (exists now)
; Consultant:Novo Nordisk:Active (exists now)
; Consultant:Boehringer and Ingelheim:Active (exists now)
; Consultant:Bayer:Active (exists now)
; Consultant:Alexion:Active (exists now)
| Iris Beldhuis:DO have relevant financial relationships
;
Research Funding (PI or named investigator):Dutch Heart Foundation:Active (exists now)
; Research Funding (PI or named investigator):Novartis:Active (exists now)
| Pardeep Jhund:DO have relevant financial relationships
;
Speaker:Novartis:Past (completed)
; Speaker:ProAdwise Communications:Past (completed)
; Research Funding (PI or named investigator):Roche Diagnostics:Active (exists now)
; Research Funding (PI or named investigator):Analog Devices Inc:Active (exists now)
; Research Funding (PI or named investigator):AstraZeneca:Past (completed)
; Speaker:Intas Pharmaceuticals:Past (completed)
; Speaker:Sun Pharmaceuticals:Past (completed)
; Other (please indicate in the box next to the company name):Novo Nordisk - clinical trial work:Active (exists now)
; Other (please indicate in the box next to the company name):Bayer - clinical trial work:Active (exists now)
; Other (please indicate in the box next to the company name):Astrazeneca - clinical trial work:Active (exists now)
; Other (please indicate in the box next to the company name):Novartis - clinical trial work:Past (completed)
; Speaker:AstraZeneca:Past (completed)
; Advisor:Novartis:Past (completed)
| Finnian Mc Causland:DO have relevant financial relationships
;
Research Funding (PI or named investigator):Lexicon:Active (exists now)
; Other (please indicate in the box next to the company name):Rubin-Anders Scientific (expert witness):Active (exists now)
; Consultant:Zydus:Active (exists now)
; Consultant:GSK:Active (exists now)
; Research Funding (PI or named investigator):NIDDK:Active (exists now)
; Research Funding (PI or named investigator):Novartis:Active (exists now)
| Inder Anand:DO NOT have relevant financial relationships
Manandhar Srista, Taylor Yhenneko, Bosworth Hayden, Pokharel Yashashwi, Chhetri Sunit, Sutton Danielle, Saha Animita, Kaur Suneet, Brown Josh, Moore Justin, Callahan Kate, Williamson Jeff
