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c or r e sp ondence

Spironolactone for Heart Failure

with Preserved Ejection Fraction
No potential conflict of interest relevant to this letter was reTo the Editor: The Treatment of Preserved Carported.
diac Function Heart Failure with an Aldosterone
Antagonist (TOPCAT) trial reported by Pitt et al. 1. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for
heart failure with preserved ejection fraction. N Engl J Med
(April 10 issue)1 is the latest neutral trial of phar- 2014;370:1383-92.
macologic therapy for heart failure with a preserved 2. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused upejection fraction. As with previous landmark tri- date incorporated into the ACC/AHA 2005 Guidelines for the
Diagnosis and Management of Heart Failure in Adults: a report
als on this subject, the diagnostic criteria of the of the American College of Cardiology Foundation/American
American College of Cardiology and the Ameri- Heart Association Task Force on Practice Guidelines: developed
can Heart Association2 (i.e., a clinical diagnosis in collaboration with the International Society for Heart and
Lung Transplantation. Circulation 2009;119(14):e391-e479.
of heart failure and an ejection fraction >45%) 3. Paulus WJ, Tschpe C, Sanderson JE, et al. How to diagnose
were used to recruit patients. These criteria differ diastolic heart failure: a consensus statement on the diagnosis
from the more stringent criteria of the European of heart failure with normal left ventricular ejection fraction by
the Heart Failure and Echocardiography Associations of the EuSociety of Cardiology, which mandate the addi- ropean Society of Cardiology. Eur Heart J 2007;28:2539-50.
tional identification of an abnormality of left 4. Shah AM, Shah SJ, Anand IS, et al. Cardiac structure and
function in heart failure with preserved ejection fraction: baseventricular diastolic relaxation.3
line findings from the echocardiographic study of the Treatment
The potential importance of this disparity has of Preserved Cardiac Function Heart Failure with an Aldosterone
been outlined by echocardiographic substudies Antagonist trial. Circ Heart Fail 2014;7:104-15.
of samples obtained from the cohorts of both 5. Persson H, Lonn E, Edner M, et al. Diastolic dysfunction in
heart failure with preserved systolic function: need for objective
TOPCAT4 and the Candesartan in Heart Failure: evidence:results from the CHARM Echocardiographic SubstudyAssessment of Reduction in Mortality and Mor- CHARMES. J Am Coll Cardiol 2007;49:687-94.
bidityPreserved trial,5 which showed that 34% DOI: 10.1056/NEJMc1405715
and 33% of the respective samples would not
have qualified for the diagnosis of heart failure
with a preserved ejection fraction, and subse- To the Editor: The TOPCAT trial raises two
quent trial inclusion, had the criteria of the Eu- concerns. First, not all the patients who were enropean Society of Cardiology been used.
Given the lack of progress in this area despite
this weeks letters
more than a decade of endeavor, is it now time
179 Spironolactone for Heart Failure with Preserved
for the international cardiology community to
agree on the definition of heart failure with a
Ejection Fraction
preserved ejection fraction? Without this, there
182 Renal Denervation for Resistant Hypertension
is surely doubt over the selection of appropriate
patients for trials and, therefore, the accurate
184 Multitarget Stool DNA Testing for Colorectalassessment of the efficacy of putative therapies.
Cancer Screening
Jonathan R. Dalzell, M.B., Ch.B., M.D.
188 Interferon Alfa Therapy in CALR-Mutated
Golden Jubilee National Hospital
Glasgow, United Kingdom
j.dalzell@nhs.net

Essential Thrombocythemia

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rolled met the criteria for a diagnosis of heart

failure. They had at least one sign and symptom
of heart failure, but they did not all meet objective criteria of diastolic heart failure such as
impaired indexes of diastolic function. The
TOPCAT investigators confirmed this in a previous article.1
Second, since myocardial fibrosis is the most
important determinant of cardiac dysfunction in
patients with heart failure, the efficacy of aldosterone inhibitors with respect to clinical outcomes in patients with diastolic heart failure
depends on whether myocardial fibrosis has developed and, if so, the extent of myocardial fibrosis when aldosterone inhibitors are received.
Accordingly, measurement of late gadolinium
enhancement should be used to stratify patients
according to the extent of fibrosis. Experiments
in rat models of hypertrophic cardiomyopathy
representing a typical diastolic heart failure pattern have shown that aldosterone inhibitors reduce and prevent myocardial fibrosis and improve diastolic function when administered at
an early stage of the disease.2-4 A prospective
study on the efficacy of spironolactone administered early in diastolic heart failure would be
very interesting.
Georgios K. Efthimiadis, M.D.
Thomas Zegkos, M.D.
Haralampos Karvounis, M.D.
American Hellenic Educational Progressive Association
University Hospital
Thessaloniki, Greece
efthymos@med.auth.gr
No potential conflict of interest relevant to this letter was reported.
1. Shah AM, Shah SJ, Anand IS, et al. Cardiac structure and

function in heart failure with preserved ejection fraction:

baseline findings from the echocardiographic study of the

Treatment of Preserved Cardiac Function Heart Failure with

an Aldosterone Antagonist trial. Circ Heart Fail 2014;7:10415.
2. Tsybouleva N, Zhang L, Chen S, et al. Aldosterone, through
novel signaling proteins, is a fundamental molecular bridge
between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy. Circulation 2004;109:1284-91.
3. de Resende MM, Kriegel AJ, Greene AS. Combined effects of
low-dose spironolactone and captopril therapy in a rat model of
genetic hypertrophic cardiomyopathy. J Cardiovasc Pharmacol
2006;48:265-73.
4. MacDonald KA, Kittleson MD, Kass PH, White SD. Effect of
spironolactone on diastolic function and left ventricular mass in
Maine Coon cats with familial hypertrophic cardiomyopathy.
J Vet Intern Med 2008;22:335-41.
DOI: 10.1056/NEJMc1405715

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To the Editor: Pitt et al. investigate the outcomes of spironolactone treatment in patients
who had heart failure with a preserved ejection
fraction. Spironolactone had no effect on the
composite outcomes in patients in the hospitalization stratum (hazard ratio, 1.01; 95% confidence interval [CI], 0.84 to 1.21; P=0.92), whereas it showed benefit in patients in the brain
natriuretic peptide (BNP) stratum (hazard ratio,
0.65; 95% CI, 0.49 to 0.87; P=0.003). The authors
speculate that this could be a chance finding or
could be due to differences in baseline characteristics between these two strata. BNP and N-terminal pro-BNP have been shown to be associated
with left ventricular remodeling.1 Therefore, it is
not surprising that a significant treatment effect
with spironolactone was seen in patients with elevated levels of BNP. Heart failure with a preserved ejection fraction is characterized by a
complex pathophysiology that affects heterogeneous patient populations.2 It is unlikely that patients history of hospitalization within the previous 12 months would help to discriminate
between patients who had true heart failure with
a preserved ejection fraction and those who had
symptoms due to other causes. Future studies on
heart failure with a preserved ejection fraction
should include markers of ventricular fibrosis
and remodeling such as galectin-3 and growth
differentiation factor 15 to identify patients who
may benefit from spironolactone treatment.3,4
Nilay Kumar, M.D.
Cambridge Health Alliance
Cambridge, MA
nikumar@challiance.org

Neetika Garg, M.D.

Beth Israel Deaconess Medical Center
Boston, MA
No potential conflict of interest relevant to this letter was reported.
1. Fertin M, Dubois E, Belliard A, Amouyel P, Pinet F, Bauters

C. Usefulness of circulating biomarkers for the prediction of left

ventricular remodeling after myocardial infarction. Am J Cardiol
2012;110:277-83.
2. Paulus WJ, Tschpe C. A novel paradigm for heart failure
with preserved ejection fraction: comorbidities drive myocardial
dysfunction and remodeling through coronary microvascular
endothelial inflammation. J Am Coll Cardiol 2013;62:263-71.
3. Izumiya Y, Hanatani S, Kimura Y, et al. Growth differentiation
factor-15 is a useful prognostic marker in patients with heart
failure with preserved ejection fraction. Can J Cardiol 2014;30:
338-44.
4. de Boer RA, Edelmann F, Cohen-Solal A, Mamas MA, Maisel
A, Pieske B. Galectin-3 in heart failure with preserved ejection
fraction. Eur J Heart Fail 2013;15:1095-101.
DOI: 10.1056/NEJMc1405715

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correspondence

To the Editor: With regard to the article by Pitt

et al. and the accompanying editorial by McMurray and OConnor1: although mineralocorticoidreceptor antagonists showed convincing beneficial effects on mortality and hospitalization
among patients with heart failure and a reduced
ejection fraction,2 the use of spironolactone in
patients with heart failure and a preserved ejection fraction in the TOPCAT study did not significantly reduce the incidence of the primary
composite outcome of death from cardiovascular
causes, aborted cardiac arrest, or hospitalization
for the management of heart failure. A potential
explanation for this discrepancy could be that
the effects of aldosterone on gene transcription
affect endothelial and cardiac function and stiffness. Diabetes and obesity, which are major risk
factors for endothelial dysfunction and heart
failure, also may modulate the release of aldosterone in individual patients.3,4 Mineralocorticoidreceptor antagonists can increase circulating
aldosterone levels. Were the aldosterone levels
monitored in the TOPCAT study population?
The use of aldosterone synthase inhibitors might
be an interesting new therapeutic approach in the
treatment of heart failure.
Henning Morawietz, Ph.D.
Stefan R. Bornstein, M.D.
Technische Universitt Dresden
Dresden, Germany
henning.morawietz@tu-dresden.de
No potential conflict of interest relevant to this letter was reported.
1. McMurray JJV, OConnor C. Lessons from the TOPCAT trial.

N Engl J Med 2014;370:1453-4.

2. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolac-

tone on morbidity and mortality in patients with severe heart

failure. N Engl J Med 1999;341:709-17.
3. Krug AW, Kopprasch S, Ziegler CG, et al. Aldosterone rapidly induces leukocyte adhesion to endothelial cells: a new link
between aldosterone and arteriosclerosis? Hypertension 2007;
50(5):e156-e157.
4. Saha S, Schwarz PE, Bergmann S, Bornstein SR, Graessler J,
Kopprasch S. Circulating very-low-density lipoprotein from subjects with impaired glucose tolerance accelerates adrenocortical
cortisol and aldosterone synthesis. Horm Metab Res 2013;45:16972.
DOI: 10.1056/NEJMc1405715

The Authors Reply: Dalzell as well as Efthimiadis et al. suggest that we should have used more
stringent criteria requiring additional measures
of diastolic dysfunction for selecting patients in
TOPCAT. Although we acknowledge that the use

of these additional inclusion criteria would have

narrowed the broad phenotype of heart failure
with a preserved ejection fraction, measures of
diastolic dysfunction are not part of the epidemiologic criteria for this syndrome. Moreover,
abnormalities of diastolic function are common
among elderly persons in the community and do
not discriminate between those with symptomatic heart failure and those without it.1 Echocardiographic data from TOPCAT show a prevalence of diastolic dysfunction similar to that in
prior outcomes trials involving patients with
heart failure and a preserved ejection fraction,
and a higher proportion of our patients had left
ventricular hypertrophy, which is a more established marker of risk than the wide array of measures of diastolic dysfunction.2
Whether a subgroup defined by a greater extent of fibrosis would have a differential response to spironolactone, as suggested by Efthimiadis et al., remains an open and interesting
question, since in the Randomized Aldactone
Evaluation Study (RALES) there was a suggestion of the increased effectiveness of spironolactone in patients with a reduced ejection fraction
and biomarkers associated with increased fibrosis.3 However, no cardiac structural assessments
of fibrosis were obtained in TOPCAT. Whether
natriuretic peptides or other biomarkers such as
galectin-3 or growth differentiation factor 15, as
suggested by Kumar and Garg, or aldosterone
levels (though they were not particularly informative in RALES4), as suggested by Morawietz
and Bornstein, would both narrow the phenotype of heart failure and a preserved ejection
fraction and result in the increased effectiveness
of mineralocorticoid-receptor antagonists or aldosterone synthase inhibitors are important hypotheses for additional studies. We are hopeful
that the limited serum samples that have been
obtained from our study participants will offer
some future insights into these issues.
We certainly share the frustrations of the correspondents that the current clinical syndrome
of heart failure and a preserved ejection fraction
is quite broadly defined5 and poses a diagnostic
challenge. We agree that the field needs to characterize more specifically defined subpopulations to ascertain from rigorous randomized
trial data whether benefits from existing or new
forms of therapy can be safely achieved. Identi-

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Copyright 2014 Massachusetts Medical Society. All rights reserved.

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fying these groups and their responses to therapies will require additional cooperative efforts
such as TOPCAT.
Marc A. Pfeffer, M.D., Ph.D.
Brigham and Womens Hospital
Boston, MA

Bertram Pitt, M.D.

University of Michigan School of Medicine
Ann Arbor, MI

Sonja M. McKinlay, Ph.D.

New England Research Institutes
Watertown, MA
Since publication of their article, the authors report no further potential conflict of interest.
1. Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bai-

ley KR, Rodeheffer RJ. Burden of systolic and diastolic ventricu-

of

m e dic i n e

lar dysfunction in the community: appreciating the scope of the

heart failure epidemic. JAMA 2003;289:194-202.
2. Shah AM, Shah SJ, Anand IS, et al. Cardiac structure and
function in heart failure with preserved ejection fraction: baseline findings from the echocardiographic study of the Treatment
of Preserved Cardiac Function Heart Failure with an Aldosterone
Antagonist trial. Circ Heart Fail 2014;7:104-15.
3. Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of
excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the Randomized Aldactone
Evaluation Study (RALES). Circulation 2000;102:2700-6. [Erratum, Circulation 2001;103:476.]
4. Rousseau MF, Gurn O, Duprez D, et al. Beneficial neurohormonal profile of spironolactone in severe congestive heart
failure: results from the RALES neurohormonal substudy. J Am
Coll Cardiol 2002;40:1596-601.
5. Shah AM, Pfeffer MA. The many faces of heart failure with
preserved ejection fraction. Nat Rev Cardiol 2012;9:555-6.
DOI: 10.1056/NEJMc1405715

Renal Denervation for Resistant Hypertension

To the Editor: In their article on the SYMPLICITY
HTN-3 study, Bhatt et al. (April 10 issue)1 report
that renal-artery denervation did not reduce blood
pressure in patients with resistant hypertension, as
compared with a control sham procedure. We suggest that technical aspects of the procedure could
explain in part the negative findings of the study.
With the first-generation Symplicity catheter,
the number and sites of delivery of radiofrequency
energy are left to the operators choice. Also,
contact with the arterial wall is detectable only
indirectly by a decrease in electric impedance, with
the consequence that the success of the procedure
may be operator-dependent. We hypothesize that
failure to obtain thermoablation rather than a
lack of antihypertensive effect of renal denervation might be mostly responsible for the negative
study results. Ideally, an effective sympathetic denervation needs to be confirmed by specific
markers or inducible events, as occurs in thermoablation in patients with cardiac arrhythmias.
Technical improvements that are aimed at
overcoming the above drawbacks and at making
the procedure more reliable and uniform are
under way. Second-generation devices that use
multielectrode devices could potentially improve
the efficacy and safety of renal denervation.2
Giuseppe Schillaci, M.D.
Enrico Boschetti, M.D.
University of Perugia at Terni
Terni, Italy
giuseppe.schillaci@unipg.it

182

No potential conflict of interest relevant to this letter was reported.

1. Bhatt DL, Kandzari DE, ONeill WW, et al. A controlled trial

of renal denervation for resistant hypertension. N Engl J Med

2014;370:1393-401.
2. Bunte MC, Infante de Oliveira E, Shishehbor MH. Endovascular
treatment of resistant and uncontrolled hypertension: therapies
on the horizon. JACC Cardiovasc Interv 2013;6:1-9.
DOI: 10.1056/NEJMc1405677

To the Editor: The findings of Bhatt et al. that

showed no significant reduction in systolic blood
pressure 6 months after renal denervation in patients with resistant hypertension contradict the
results of a previous study.1 Some controversial
issues that have a potential effect on these results
deserve consideration. First, the quality of renal
denervation was not formally assessed in this
trial. Renal denervation should be performed
only by physicians who are specifically trained at
experienced centers,2 but 31% of operators had
performed only one procedure or had no previous experience with the technique. Second, patients were required to receive the maximum and
stabilized treatment for only 2 weeks, whereas
guidelines recommend at least 2 months of such
treatment.3 Furthermore, no data about changes
in treatment that could explain the improvement
in the control group during follow-up were reported. Third, 26% of patients in the study were
black and thus presented ethnic differences in
hypertension, and black patients were not includ-

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