Effect of Selective Heart Rate Slowing in Heart Failure With Preserved Ejection Fraction.
BACKGROUND
Heart failure with preserved ejection fraction (HFpEF) is associated with significant morbidity and mortality but is currently refractory to therapy. Despite limited evidence, heart rate reduction has been advocated, on the basis of physiological considerations, as a therapeutic strategy in HFpEF. We tested the hypothesis that heart rate reduction improves exercise capacity in HFpEF.


RESULTS
We conducted a randomized, crossover study comparing selective heart rate reduction with the If blocker ivabradine at 7.5 mg twice daily versus placebo for 2 weeks each in 22 symptomatic patients with HFpEF who had objective evidence of exercise limitation (peak oxygen consumption at maximal exercise [o2 peak] <80% predicted for age and sex). The result was compared with 22 similarly treated matched asymptomatic hypertensive volunteers. The primary end point was the change in o2 peak. Secondary outcomes included tissue Doppler-derived E/e' at echocardiography, plasma brain natriuretic peptide, and quality-of-life scores. Ivabradine significantly reduced peak heart rate compared with placebo in the HFpEF (107 versus 129 bpm; P<0.0001) and hypertensive (127 versus 145 bpm; P=0.003) cohorts. Ivabradine compared with placebo significantly worsened the change in o2 peak in the HFpEF cohort (-2.1 versus 0.9 mL·kg(-1)·min(-1); P=0.003) and significantly reduced submaximal exercise capacity, as determined by the oxygen uptake efficiency slope. No significant effects on the secondary end points were discernable.


CONCLUSIONS
Our observations bring into question the value of heart rate reduction with ivabradine for improving symptoms in a HFpEF population characterized by exercise limitation.


BACKGROUND
URL: http://www.clinicaltrials.gov. Unique identifier: NCT02354573.
From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK (N.P., M.M., A.Y., J.M.F., J.S.D., H.W., S.N., H.A.); School of Medicine and Dentistry, University of Aberdeen, UK (N.S., A.R., S.S., D.K.D.); and Norwich Medical School, University of East Anglia, UK (M.F.).
Nikhil
N
Pal
From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK (N.P., M.M., A.Y., J.M.F., J.S.D., H.W., S.N., H.A.); School of Medicine and Dentistry, University of Aberdeen, UK (N.S., A.R., S.S., D.K.D.); and Norwich Medical School, University of East Anglia, UK (M.F.).
Nadiya
N
Sivaswamy
From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK (N.P., M.M., A.Y., J.M.F., J.S.D., H.W., S.N., H.A.); School of Medicine and Dentistry, University of Aberdeen, UK (N.S., A.R., S.S., D.K.D.); and Norwich Medical School, University of East Anglia, UK (M.F.).
Masliza
M
Mahmod
From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK (N.P., M.M., A.Y., J.M.F., J.S.D., H.W., S.N., H.A.); School of Medicine and Dentistry, University of Aberdeen, UK (N.S., A.R., S.S., D.K.D.); and Norwich Medical School, University of East Anglia, UK (M.F.).
Arash
A
Yavari
From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK (N.P., M.M., A.Y., J.M.F., J.S.D., H.W., S.N., H.A.); School of Medicine and Dentistry, University of Aberdeen, UK (N.S., A.R., S.S., D.K.D.); and Norwich Medical School, University of East Anglia, UK (M.F.).
Amelia
A
Rudd
From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK (N.P., M.M., A.Y., J.M.F., J.S.D., H.W., S.N., H.A.); School of Medicine and Dentistry, University of Aberdeen, UK (N.S., A.R., S.S., D.K.D.); and Norwich Medical School, University of East Anglia, UK (M.F.).
Satnam
S
Singh
From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK (N.P., M.M., A.Y., J.M.F., J.S.D., H.W., S.N., H.A.); School of Medicine and Dentistry, University of Aberdeen, UK (N.S., A.R., S.S., D.K.D.); and Norwich Medical School, University of East Anglia, UK (M.F.).
Dana K
DK
Dawson
From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK (N.P., M.M., A.Y., J.M.F., J.S.D., H.W., S.N., H.A.); School of Medicine and Dentistry, University of Aberdeen, UK (N.S., A.R., S.S., D.K.D.); and Norwich Medical School, University of East Anglia, UK (M.F.).
Jane M
JM
Francis
From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK (N.P., M.M., A.Y., J.M.F., J.S.D., H.W., S.N., H.A.); School of Medicine and Dentistry, University of Aberdeen, UK (N.S., A.R., S.S., D.K.D.); and Norwich Medical School, University of East Anglia, UK (M.F.).
Jeremy S
JS
Dwight
From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK (N.P., M.M., A.Y., J.M.F., J.S.D., H.W., S.N., H.A.); School of Medicine and Dentistry, University of Aberdeen, UK (N.S., A.R., S.S., D.K.D.); and Norwich Medical School, University of East Anglia, UK (M.F.).
Hugh
H
Watkins
From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK (N.P., M.M., A.Y., J.M.F., J.S.D., H.W., S.N., H.A.); School of Medicine and Dentistry, University of Aberdeen, UK (N.S., A.R., S.S., D.K.D.); and Norwich Medical School, University of East Anglia, UK (M.F.).
Stefan
S
Neubauer
From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK (N.P., M.M., A.Y., J.M.F., J.S.D., H.W., S.N., H.A.); School of Medicine and Dentistry, University of Aberdeen, UK (N.S., A.R., S.S., D.K.D.); and Norwich Medical School, University of East Anglia, UK (M.F.).
Michael
M
Frenneaux
From Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK (N.P., M.M., A.Y., J.M.F., J.S.D., H.W., S.N., H.A.); School of Medicine and Dentistry, University of Aberdeen, UK (N.S., A.R., S.S., D.K.D.); and Norwich Medical School, University of East Anglia, UK (M.F.) houman.ashrafian@cardiov.ox.ac.uk.
Houman
H
Ashrafian
D000368:Aged; D000369:Aged, 80 and over; D058070:Asymptomatic Diseases; D001552:Benzazepines / Q000627:therapeutic use*; D015415:Biomarkers; D018592:Cross-Over Studies; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors; D004311:Double-Blind Method; D023381:Endpoint Determination; D005080:Exercise Test; D017079:Exercise Tolerance; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D000077550:Ivabradine; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010101:Oxygen Consumption / Q000187:drug effects; D012849:Sinoatrial Node / Q000187:drug effects / Q000503:physiopathology; D013318:Stroke Volume; D017211:Treatment Failure
D001552:Benzazepines; D015415:Biomarkers; D054815:Cyclic Nucleotide-Gated Cation Channels; D020097:Natriuretic Peptide, Brain; D000077550:Ivabradine
exercise; heart failure; heart rate