Download Nitrates in Heart Failure with Preserved Ejection Fraction

Correspondence
the conduct of ATMOSPHERE, communicated to Gervais Tougas, M.D.
Novartis that they were of the opinion that the R. Paul Aftring, M.D., Ph.D.
potential risk to participants with diabetes was Novartis Pharma
unacceptable and that aliskiren should be dis- Basel, Switzerland
[email protected]
continued in these patients.
Disclosure forms provided by the authors are available with
Although Novartis had empowered the data the full text of this letter at NEJM.org.
monitoring committee with safety oversight of
the trial, the company complied with the man- This letter was published on April 4, 2016, at NEJM.org.
date of the CTFG to discontinue aliskiren in
patients with diabetes. After discussion within 1. Swedberg K, Borer JS, Pitt B, Pocock S, Rouleau J. Challenges
data monitoring committees when regulatory authorities inNovartis and with the ATMOSPHERE executive to
tervene. N Eng J Med 2016;374:1580-4.
committee, Novartis adopted an approach that 2. McMurray JJ, Krum H, Abraham WT, et al. Aliskiren, enaladiscontinued the use of aliskiren in patients pril, or aliskiren and enalapril in heart failure N Engl J Med
2016;374:1521-32.
with diabetes in all countries while allowing 3. Parving H-H, Brenner BM, McMurray JJV, et al. Cardiorenal
these patients to remain in the trial, and Novar- end points in a trial of aliskiren for type 2 diabetes. N Engl J Med
tis modified the analysis plan accordingly. This 2012;367:2204-13.
4. Gheorghiade M, Böhm M, Greene SJ, et al. Effect of aliskiren
approach allowed the trial to continue to conclu- on
postdischarge mortality and heart failure readmissions
sion while protecting the integrity of the results among patients hospitalized for heart failure: the ASTRONAUT
and the rights and expectations of the partici- randomized trial. JAMA 2013;309:1125-35.
pants in the trial.
DOI: 10.1056/NEJMc1603515
Nitrates in Heart Failure with Preserved Ejection Fraction
To the Editor: In their article on the Nitrate’s
Effect on Activity Tolerance in Heart Failure with
Preserved Ejection Fraction (NEAT-HFpEF) trial,
Redfield et al. (Dec. 10 issue)1 show a significant
linear relationship between the dose of isosorbide mononitrate and daily physical activity quantified by means of accelerometers. They interpret
the findings to indicate an adverse effect of isosorbide mononitrate in patients with heart failure and a preserved ejection fraction.
We favor a different view — that the use of
isosorbide mononitrate at a dose of up to 120 mg
per day caused subtle but disabling symptoms
such as headache, malaise, and dizziness in a
cohort of obese older adults who had multiple
coexisting conditions and who were receiving
multiple antihypertensive drugs. These symptoms
reduced activity directly, and not necessarily by
aggravating cardiac failure, as implied by the
authors. A total of 16 participants discontinued
isosorbide mononitrate completely, and 9 of these
participants discontinued the study drug because
of headaches (Fig. S3 in the Supplementary Appendix of the article, available at NEJM.org).
The authors underestimate the implications of
dizziness, syncope, and presyncope if they rely
on brachial systolic blood pressure and mean
n engl j med 374;16
pressure, since organic nitrates markedly reduce
aortic and left ventricular systolic pressure while
having little effect on brachial pressure.2-4 We
remain satisfied that isosorbide mononitrate
in low doses and with appropriate monitoring
is beneficial in patients with heart failure and a
preserved ejection fraction.
Michael F. O’Rourke, M.D., D.Sc.
St. Vincent’s Clinic
Sydney, NSW, Australia
[email protected]
Michel E. Safar, M.D.
Hôpital Hôtel-Dieu
Paris, France
Wilmer W. Nichols, Ph.D.
University of Florida
Gainesville, FL
Dr. O’Rourke reports being a director of AtCor Medical, a
manufacturer of systems for analyzing the arterial pulse, and
Aortic Wrap, a developer of devices to improve aortic distensibility and analyze the arterial pulse. No other potential conflict of
interest relevant to this letter was reported.
1. Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide mono-
nitrate in heart failure with preserved ejection fraction. N Engl J
Med 2015;373:2314-24.
2. Kelly RP, Gibbs HH, O’Rourke MF, et al. Nitroglycerin has
more favourable effects on left ventricular afterload than apparent from measurement of pressure in a peripheral artery. Eur
Heart J 1990;11:138-44.
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The
n e w e ng l a n d j o u r na l
3. O’Rourke MF, Safar ME, Dzau V, eds. Arterial vasodilation:
mechanism and therapy. Edinburgh: Lea & Febiger, 1993.
4. O’Rourke RA, Shaver JA, Silverman ME. The history, physical examination, and cardiac auscultation. In: Fuster V, O’Rourke
RA, Walsh RA, et al., eds. Hurst’s the heart. 12th ed. New York:
McGraw-Hill, 2008,216-93.
DOI: 10.1056/NEJMc1601507
of
m e dic i n e
2. Gupta V, Lipsitz LA. Orthostatic hypotension in the elderly:
diagnosis and treatment. Am J Med 2007;120:841-7.
3. Shibao C, Lipsitz LA, Biaggioni I. Evaluation and treatment
of orthostatic hypotension. J Am Soc Hypertens 2013;7:317-24.
4. Rubenstein LZ. Falls in older people: epidemiology, risk fac-
tors and strategies for prevention. Age Ageing 2006;35:Suppl 2:
ii37-41.
DOI: 10.1056/NEJMc1601507
To the Editor: Redfield et al. report decreased
levels of physical activity with nitrate therapy in
patients with heart failure and a preserved ejection fraction. Orthostatic hypotension might
have limited the daily activities of these patients,
because exercise capacity was similar in patients
who received placebo and those who received isosorbide mononitrate. Patients with heart failure
and a preserved ejection fraction may be susceptible to hypotension and reduced cardiac output
during nitrate therapy.1
Although presyncope and syncope were
among the safety outcomes in this trial, many
elderly patients do not report these symptoms
even though they have orthostatic hypotension.2
Some elderly patients report fatigue on standing;
this fatigue quickly resolves after the person sits
or lies down.3 In such patients, fatigue may
erroneously be considered to be a symptom of
heart failure.
Orthostatic hypotension may also result in
falls or fear of falls.4 As a result, patients with
orthostatic hypotension may limit their activity.
It seems that changes in orthostatic blood pressure were not assessed and only in-office bloodpressure measurements were performed in this
trial. We suggest that a more detailed investigation regarding symptoms of orthostatic hypotension with inclusion of falls as a safety outcome is needed to better interpret the findings
of this trial.
Fatih Tufan, M.D.
Timur Akpinar, M.D.
M. Akif Karan, M.D.
Istanbul University
Istanbul, Turkey
[email protected]
No potential conflict of interest relevant to this letter was reported.
1. Schwartzenberg S, Redfield MM, From AM, Sorajja P,
Nishimura RA, Borlaug BA. Effects of vasodilation in heart failure with preserved or reduced ejection fraction implications of
distinct pathophysiologies on response to therapy. J Am Coll
Cardiol 2012;59:442-51.
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n engl j med 374;16
To the Editor: Nitrates reduce intracardiac filling pressures by lowering cardiac preload and
afterload.1,2 Accordingly, high-dose nitrates are
effective in decreasing shortness of breath, increasing the oxygen saturation, and improving
other outcome measures in patients with acute
heart failure, a condition characterized by increased intracardiac filling pressures.1,2
The majority of the patients in the trial reported by Redfield et al. apparently had normal
intracardiac filling pressures, as suggested by
median N-terminal pro–brain natriuretic peptide
(NT-proBNP) plasma concentrations of 248 pg
per milliliter in the placebo-first group and
210 pg per milliliter in the isosorbide mononitrate–first group; these values were only approximately half the lower enrollment limit for
the targeted level of NT-proBNP (>400 pg per
milliliter).3 Of note, resting brain natriuretic
peptide (BNP) and NT-proBNP plasma concentrations also reliably predict a cardiac cause of
dyspnea during exertion (and therefore increased
intracardiac filling pressures during exercise).3
Can the authors explain the postulated mechanisms by which nitrates could have increased
daily activity in patients with presumably normal intracardiac filling pressures? Also, at the
time of randomization, what percentage of patients had documented increased intracardiac
filling pressures as measured through a pulmonary-artery catheter? Finally, can the authors explain the substantial increase in the NT-proBNP
plasma concentration during the course of the
trial?
Nikola Kohzuharov, M.D.
Zaid Sabti, M.D.
Christian Mueller, M.D.
University Hospital Basel
Basel, Switzerland
[email protected]
No potential conflict of interest relevant to this letter was reported.
1. Mebazaa A, Yilmaz MB, Levy P, et al. Recommendations on
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Correspondence
pre-hospital & early hospital management of acute heart failure:
a consensus paper from the Heart Failure Association of the
European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine. Eur J Heart Fail 2015;17:544-58.
2. Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of
high-dose isosorbide dinitrate plus low-dose furosemide versus
high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet 1998;351:389-93.
3. Mueller C, Maeder MT, Christ A, et al. B-type natriuretic
peptides for the evaluation of exercise intolerance. Am J Med
2009;122:265-72.
DOI: 10.1056/NEJMc1601507
high. The physiological basis for and the high
frequency of elevated filling pressures despite
normal BNP assay levels in patients with heart
failure and a preserved ejection fraction have
been well described.3,4 Owing to the insensitivity
of BNP assays to hemodynamic abnormalities in
patients with heart failure and a preserved ejection fraction, patients were permitted to enter
the trial without elevated BNP assay levels if they
had other objective evidence of heart failure.
Although a significant percentage of patients
were enrolled in centers that routinely perform
right heart catheterization in patients with heart
failure and a preserved ejection fraction, the
case-report forms did not capture these data.
On average, the increase in the NT-proBNP
level was 56 pg per milliliter higher in patients
who received isosorbide mononitrate than in
those who received placebo. Although this trend
was not significant and could have occurred by
chance, the potential for emerging counterregulatory neurohumoral activation and intravascular
volume expansion (commonly referred to as
“nitrate pseudo-tolerance”) could have contributed to increases in NT-proBNP levels with the
use of nitrate therapy.
The authors reply: O’Rourke et al. and Tufan
et al. emphasize the potential for the development of hypotension in patients who receive nitrates, and they ascribe the decreases in daily
activity observed with the use of isosorbide mononitrate in the NEAT-HFpEF trial to adverse side
effects. We concur with this interpretation. The
effect of nitrates in the context of the unique
pathophysiology of heart failure with preserved
ejection fraction, with the potential for beneficial
or detrimental effects, provided the equipoise for
our trial.1 In the discussion of our results, we
stated that “Our post hoc analysis indicated decreases in blood pressure with isosorbide mononitrate. In addition, the potential for drug inter- Margaret M. Redfield, M.D.
actions and adverse drug reactions increases
Mayo Clinic
with older age, obesity, coexisting illnesses, and Rochester, MN
polypharmacy, all of which are characteristic of [email protected]
our study population.” These statements are Eric J. Velazquez, M.D.
consistent with the stated concerns regarding
Duke Clinical Research Institute
hypotension and careful assessment of side ef- Durham, NC
fects in elderly patients. Furthermore, we speculated that the measures of daily activity used in Eugene Braunwald, M.D.
our trial provided a new and highly sensitive Harvard Medical School
Boston, MA
measure of the global effect of isosorbide monoSince publication of their article, the authors report no furnitrate in the participants.
ther potential conflict of interest.
O’Rourke et al. also raise the potential for
benefit with lower doses of nitrates. The maxi- 1. Zakeri R, Levine JA, Koepp GA, et al. Nitrate’s effect on acmal dose of isosorbide mononitrate targeted in tivity tolerance in heart failure with preserved ejection fraction
rationale and design. Circ Heart Fail 2015;8:221-8.
our trial was based on studies involving patients trial:
2. Gunasekara NS, Noble S. Isosorbide 5-mononitrate: a review
with angina in whom doses of 120 mg or 240 mg of a sustained-release formulation (Imdur) in stable angina pecper day significantly increased exercise time at toris. Drugs 1999;57:261-77.
Anjan VY, Loftus TM, Burke MA, et al. Prevalence, clinical
6 weeks, whereas lower doses did not.2 The 3.
phenotype, and outcomes associated with normal B-type natridose–response analysis in our trial suggested uretic peptide levels in heart failure with preserved ejection fracprogressive decreases in activity starting with tion. Am J Cardiol 2012;110:870-6.
4. Iwanaga Y, Nishi I, Furuichi S, et al. B-type natriuretic pepthe 30-mg dose.
tide strongly reflects diastolic wall stress in patients with chronKohzuharov et al. raise concern that patients ic heart failure: comparison between systolic and diastolic heart
enrolled in our trial did not have elevated filling failure. J Am Coll Cardiol 2006;47:742-8.
pressures, since BNP levels were not uniformly DOI: 10.1056/NEJMc1601507
n engl j med 374;16
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