Download Primary Care Update

Primary Care Update
January 26 & 27, 2017
New Approaches for Systolic Heart Failure
Thomas Cimato, MD, PhD, FACC, FAHA
Associate Professor
Division of Cardiovascular Medicine
Educational Goals:
• Review the definition, diagnostic
criteria and medical therapy for
congestive heart failure
• Understand why sacubatril-valsartan is
superior to ACE inhibitor therapy in
chronic systolic heart failure
• Understand the benefits and adverse
reactions of sacubatril-valsartan
therapy in patients with systolic heart
failure
Question 1:
Sacubatril-valsartan is recommended in
patients with NYHA Class II-III systolic
congestive heart failure who can tolerate
an ACE inhibitor or ARB with prior
hospitalization in the past 12 months?
A. True
B. False
Question 2:
Therapy with sacubatril-valsartan
reduces hospitalization for congestive
heart failure?
A. True
B. False
Question 3:
Which of the following statements
regarding use of sacubatril-valsartan
treatment are true?
A. It can cause angioedema
B. It cannot be given with an ACEi or ARB
C. It cannot be used in patients with
systolic blood pressure < 100 mm Hg
D. It cannot be used in patients with
eGFR < 30
E. All of the above
Congestive Heart FailureDefinition
• A disorder of EITHER cardiac filling
(diastole) or contraction (systole)
resulting in symptoms of shortness of
breath
• How do we know that the shortness of
breath is due to heart failure and not
another cause? What are the criteria for
the diagnosis of heart failure?
Congestive Heart Failure-Definition
Yturralde and Gaasch (2005) Prog Cardiovasc Dis 47(5): 314-9
e
l
red
BNP Levels in Diagnosis
REVIEW
of Heart Failure
B-type natriuretic peptide (ng/L)
1400
1200
1000
800
600
400
200
0
No congestive
heart failure
(n=770)
Dyspnoea due to
non-cardiac causes in
patients with a history
of left-ventricular
dysfunction (n=72)
Dyspnoea due
to congestive
heart failure
(n=744)
Figure 2: BNP concentrations in patients presenting with
dyspnoea and enrolled in the BNP multinational study
Guideline Directed Therapy
for Congestive Heart Failure
Guideline-Directed Medical Therapy – “GDMT”
I IIa IIb III
Adapted from Yancy et al, Circulation 2013
Intensive Review of Cardiology
COMBINED NEPRILYSIN AND RAS
INHIBITION FOR TREATMENT OF HEART FAILURE
JCHF. 2014;2(6):663-670. doi:10.1016/j.jchf.2014.09.001
Sacubatril-Valsartan Inhibits
Degradation of BNP
• SOLVDwasthe
OnlytrialinHF
Toshowasignificant
reductioninmortality
WithanACEinhibitor
Angiotensin–Neprilysin Inhibition versus Enalapril
in Heart Failure
n e w e ng l a n d j o u r na
John J.V. McMurray, M.D., Milton Packer, M.D., Akshay S. Desai, M.D., M.P.H., Jianjian Gong, Ph.D.,
The
Martin P. Lefkowitz, M.D., Adel R. Rizkala, Pharm.D., Jean L. Rouleau, M.D., Victor C. Shi, M.D.,
Scott D. Solomon, M.D., Karl Swedberg, M.D., Ph.D., and Michael R. Zile, M.D.,
for the PARADIGM-HF Investigators and Committees*
A BS T R AC T
hospitalizationforCHF
From the British Heart Foundation (BHF)
Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
(J.J.V.M.); the Department of Clinical Sciences, University of Texas Southwestern
Medical Center, Dallas (M.P.); the Division of Cardiovascular Medicine, Brigham
and Women’s Hospital, Boston (A.S.D.,
S.D.S.); Novartis Pharmaceuticals, East
Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.);
Institut de Cardiologie de Montréal, Université de Montréal, Montreal (J.L.R.);
the Department of Molecular and Clinical Medicine, University of Gothenburg,
Gothenburg, Sweden (K.S.); National
Heart and Lung Institute, Imperial College London, London (K.S.); and the
Medical University of South Carolina and
Ralph H. Johnson Veterans Affairs Medical Center, Charleston (M.R.Z.). Address
reprint requests to Dr. Packer at the Department of Clinical Sciences, University
of Texas Southwestern Medical Center,
5323 Harry Hines Blvd., Dallas, TX 75390,
or at [email protected];
or to Dr. McMurray at the BHF Cardiovascular Research Centre, University Pl.,
University of Glasgow, Glasgow, Scotland
G12 8QQ, United Kingdom, or at john
[email protected].
* A complete list of the investigators in
the Prospective Comparison of ARNI
[Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–
Enzyme Inhibitor] to Determine Impact
on Global Mortality and Morbidity in
Heart Failure Trial (PARADIGM-HF) is
provided in the Supplementary Appendix, available at NEJM.org.
Drs. McMurray and Packer contributed
equally to this article.
This article was published on August 30,
2014, and updated on September 11, 2014,
at NEJM.org.
Methods
Cumulative Probability
1.0 receptor–neprilysin inhibitor LCZ696 with enalapril
We compared the angiotensin
Hazard
0.80
(95%
in patients who had heart failure with a reduced ejection
fraction. ratio,
In previous
studies, enalapril improved survival in such patients.
P<0.001
0.6
In this double-blind trial, we randomly assigned 8442 patients with class II, III, or
0.5 fraction of 40% or less to receive either LCZ696 (at
IV heart failure and an ejection
a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy.
0.4 The primary outcome was a composite of death from
cardiovascular causes or hospitalization for heart failure, but the trial was designed
to detect a difference in the rates of death from cardiovascular causes.
Results
0.3
C
Hospitalization
HearttheFailure
LCZ696 was
superior to enalaprilfor
in reducing
risks of death and of hospitalization for heart failure. (Funded
by
Novartis;
PARADIGM-HF
ClinicalTrials.gov num1.0
ber, NCT01035255.)
Hazard ratio, 0.79 (95%
1.0
CI, 0.73–0.87)
Enalapril
0.2according to prespecified rules, after a median followThe trial was stopped early,
up of 27 months, because the boundary for an overwhelming benefit with LCZ696
had been crossed. At the0.1
time of study closure, the primary outcome had occurred
in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the
enalapril group (hazard 0.0
ratio in the LCZ696 group, 0.80; 95% confidence interval
[CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835
0
180
360
540
720
900
patients (19.8%) receiving enalapril died (hazard ratio for death from any cause,
0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%),
Days
since
respectively, died from cardiovascular causes (hazard
ratio,
0.80; Randomization
95% CI, 0.71 to
0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospiNo.foratheart
Risk
talization
failure by 21% (P<0.001) and decreased the symptoms and
physicalLCZ696
limitations of heart4187
failure (P 3922
= 0.001). The
LCZ696 group
3663
3018had higher
2257 pro-1544
portions
of
patients
with
hypotension
and
nonserious
angioedema
but
lower pro-1488
Enalapril
4212 3883 3579 2922 2123
portions with renal impairment, hyperkalemia, and cough than the enalapril group.
Conclusions
B Death from Card
LCZ696
1080
896
853
Cumulative Probability
A Primary End Point DeathCVcausesor
Background
CI, 0.71–0.89)
0.5
0.4
0.3
0.2
0.1
0.0
1260
249
236
0.6
0
No. at Risk
LCZ696
Enalapril
4187
4212
D Death from Any
1.0
Neprilysin
Inhibition — A Novel Therapy for Heart Failure
editorials
Mariell Jessup, M.D.
U.
S.
-T
AH
D
LV
SO
EF
M
T
AD
IT
-C
RT
SH
EM
IF
PH
T
AS
PA
I
RA S-H
F
D
IG
M
-H
F
Ca
rv
ed
ilo
lG
ro
up
No. Needed to Treat to Reduce
Death from Any Cause
other noteworthy, successful trials
The Food
In PARADIGM-HF (Prospective Comparison of
250 (FDA) last
1)3-5Drug
? TheAdministration
with heart failure
(Tableand
approved
220 [Angiotensin Receptor–Neprilysin Inhibitor]
included patients
witha new
New oral
Yorkdrug (hydralazine–isosor- ARNI
dinitrate)
patients with heart failure and with ACEI [Angiotensin-Converting–Enzyme Ination class II,bide
III, or
IV heartfor
failure
200
a reduced
fraction in 2005 — and this hibitor] to Determine Impact on Global Morejection fraction
of lessejection
than 40%
changed to drug
35% was
or recommended
less by an only for150self-identified tality and Morbidity in Heart Failure Trial),
black patients who continued to have symptoms McMurray et al. report that LCZ696, as comto the protocol)
and who were redespite evidence-based treatment.1 The aldoste- pared with a target-dose enalapril-based regibest available medical therapy. The
100
rone antagonist eplerenone was approved
for the men, significantly reduced the rates of death
o participated in PARADIGM-HF
treatment of heart failure in 2003. (In 2012, the from any72 cause and from cardiovascular causes
to those in other studies involving
European Medicines Agency approved
for worsening
50 ivabradine, and the rates34of hospitalizations
35
h mild to moderately severe heart
26
which has not received FDA approval.)
23 a heart failure in patients with a reduced ejection
22 Now,
novel drug, LCZ696, a dual inhibitor of angioten- fraction. In addition, patients’ quality of life, as
0
LCZ696 succeed in improving outsin II receptor and neprilysin, may prove to be the measured on the Kansas City Cardiomyopathy
onvincingly in
this
representative
first
disruptive
agent to the heart-failure treat- Questionnaire, was significantly improved.2
of patients? Drugs
that inhibitwhich
the has remained essentially
Who were the patients in this remarkable
ment algorithm,
tensin–aldosterone
system
(RAAS)
trial, and how do they compare with the patients
unchanged for a decade.
oundational to cardiovascular drug
almost
three decades. RAAS inhibiable 1. Mean Baseline Characteristics of Patients with Heart Failure and a Reduced Ejection Fraction in Five Trials.*
Figure 1. Numbers of Patients with Heart Failure
te vasoconstriction, myocyte hyperWho Would Need to Be Treated
Reduce Any-Cause
SystolictoBlood
myocardial fibrosis, Left
an Ventricular
effect that
ial
Age
Ejection Fraction NYHA
Class in Seven
HeartClinical
Rate Trials.
Pressure
Treatment
Mortality
ed into clinically meaningful imSOLVD-T denotes Studies of Left Ventricular Dysfunction–
ACE
MineraloICD with
in functional status and survival.
study are BetaTreatment.9 The data for the MADIT-CRTInhibitor
corticoid
or without
peptides, which include atrial natrior ARB of Blocker
Antagonist
CRT
from the initial report, with an average follow-up
de, B-type natriuretic
peptide,
and % of2.5
years.
yr
%
patients
beats/min
mm Hg
% of patients
re
secreted
by
the
heart,
vasculature,
HEFT
57
24
95 in class III
NA
126
87
74
38
18
central nervous system in response
ADIT-CRT
65
24
85 in class II
NA
122
97
93
31
100
cardiac-wall stress and other stimHIFT
60
29
49 in class II;
79
121
91
89
60
5
during the run-in
phase because
of an
adverse
tic peptides have
potent natriuretic
50 in class III
Angiotensin Receptor Neprilysin Inhibition Compared With
Enalapril on the Risk of Clinical Progression in Surviving
Patients With Heart Failure
Milton Packer, CumulativeHospitalizations
MD*; John J.V. McMurray, MD*; Akshay S. Desai, MD, MPH;
Cumulative Number of Hospitalizations
for Heart Failure per 100 Patients
Jianjian Gong, PhD; Martin P. Lefkowitz, MD; Adel R. Rizkala, PharmD; Jean L. Rouleau, MD;
Victor C. Shi, MD; Scott D. Solomon, MD; Karl Swedberg, MD, PhD; Michael Zile, MD;
60MD, PhD; Juan Luis Arango, MD; J. Malcolm Arnold, MD; Jan Bĕlohlávek, MD, PhD;
Karl Andersen,
Michael Böhm, MD; Sergey
Boytsov,
MD;
Lesley
J. Burgess, MBBCh, PhD; Walter Cabrera, MD;
Rate
ratio
0.77
(0.67-0.89)
Carlos Calvo, MD; Chen-Huan Chen,
MD;
Andrej
Dukat, MD; Yan Carlos Duarte, MD;
P < 0.001
Andrejs Erglis, MD, PhD; Michael Fu, MD; Efrain Gomez, MD; Angel Gonzàlez-Medina, MD;
Albert A. Hagège, MD, PhD; Jun Huang, MD; Tzvetana Katova, PhD; Songsak Kiatchoosakun, MD;
Kee-Sik Kim, MD, PhD; Ömer Kozan, Prof Dr; Edmundo Bayram Llamas, MD; Felipe Martinez, MD;
Bela Merkely, MD; Iván Mendoza, MD; Arend Mosterd, MD, PhD; Marta Negrusz-Kawecka, MD, PhD;
Keijo40
Peuhkurinen, MD; Felix J.A. Ramires,
MD, PhD; Jens Refsgaard, MD, PhD;
Enalapril
Arvo Rosenthal, MD, PhD; Michele Senni, MD; Antonio S. Sibulo Jr, MD; José Silva-Cardoso, MD, PhD;
Iain B. Squire, MD; Randall C. Starling, MD, MPH; (n=4212)
John R. Teerlink, MD; Johan Vanhaecke, MD, PhD;
Dragos Vinereanu, MD, PhD; Raymond Ching-Chiew Wong, MBBS; on behalf of the PARADIGM-HF
Investigators and Coordinators†
LCZ696
20
(n=4187)
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
Received October 11, 2014; accepted October 20, 2014.
From the Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX (M.P.); BHF Cardiovascular Research Centre, University
of Glasgow, Glasgow, Scotland, UK (J.J.V.M.); Brigham and Women’s Hospital, Cardiovascular Medicine, MA (A.S.D., S.D.S.); Novartis Pharmaceutical
Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Université de Montréal, Institut de Cardiologie, Montréal, Canada (J.L.R.); Department of Molecular
and Clinical Medicine, Gothenburg, Sweden (K.S.); The Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center,
Charleston, SC (M.Z.); School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland (K.A.); Unidad de Cirugía Cardiovascular de
Guatemala, Guatemala City, Guatemala (J.L.A); Western University, Department of Medicine and Physiology, Ontario, Canada (J.M.A.); 2nd Department of
Medicine, Cardiovascular Medicine, General University Hospital and 1st Medical School, Charles University in Prague, Prague, Czech Republic (J.B.); Department
of Cardiology, University of the Saarland, Homburg/Saar, Germany (M.B.); National Research Center for Preventive Medicine, Moscow, Russia (S.B.); TREAD
Research, Cardiology Unit, Department of Internal Medicine, Stellenbosch University and Tygerberg Hospital, Parow, South Africa (L.J.B.); Clinica Vesalio, Lima,
Peru (W.C.); Unidad de Hipertensión Arterial y Riesgo Vascular, Hospital Clínico Universitario, Santiago de Compostela, A Coruña, Spain (C.C.); Department of
Medicine, National Yang-Ming University, Taiwan, Republic of China (C.-H.C.); Second Department of Internal Medicine, Comenius University in Bratislava,
Bratislava, Slovakia (A.D.); Luis Vernaza Hospital, Guayaquil, Ecuador (Y.C.D.); Faculty of Medicine, Institute of Cardiology, University of Latvia, Riga, Latvia
(A.E.); Department of Medicine, Sahlgrenska University Hospital/Ӧstra Hospital, Göteborg, Sweden (M.F.); Clinica Shaio, Bogota, Colombia (E.G.); Hospiten
Risk
SantoPatients
Domingo,at
Universidad
Autonoma de Santo Domingo, Santo Domingo, Dominican Republic (A.G.-M.); Assistance Publique Hôpitaux de Paris, Hôpital
Européen Georges Pompidou, Département de Cardiologie; Paris Descartes University, Sorbonne Paris Cité; INSERM U970, Paris Cardiovascular Research
4054Hospital with
LCZ696
4187
3885
3276University,
2472
1001
279Sofia, Bulgaria
12(T.K.);
Center; Paris, France (A.A.H.); First Affiliated
Nanjing Medical
China (J.H.);1710
National Hospital
of Cardiology,
Enalapril
4212
4049
3857
3228
2408
1724
993
278 University Medicine
17
Cardiology, Medicine, Khon Kaen University, Thailand (S.K.); Daegu Catholic University Hospital, Daegu, Korea (K.-S.K.); Dokuz Eylül
4140
Faculty, İzmir, Turkey (O.K.); Fundación Cardiovascular de Aguascalientes A.C., Hidalgo, Mexico (E.B.L.); Titular de Medicina Interna, Universidad Nacional
4143
de Córdoba, Instituto DAMIC/Fundacion Rusculleda, Cordoba, Argentina (F.M.); Heart and Vascular Center Semmelweis University, Budapest, Hungary (B.M.);
Circulation.2015;131:54–61.DOI:10.1161/CIRCULATIONAHA.114.013748
Venezuela Instituto Tropical Medicine Universidad Central Venezuela, Caracas, Venezuela (I.M.); Department of Cardiology, Meander Medical Centre, Amersfoort
and WCN Dutch Network for Cardiovascular Research, Utrecht, The Netherlands (A.M.); Department and Clinic of Cardiology, Wroclaw Medical University,
Poland (M.N.-K.); Department of Medicine, Kuopio University Hospital, Kuopio, Finland (K.P.); Heart Institute (InCor) – University of São Paulo, Medical
School, Brazil (F.J.A.R.); Department of Cardiology, Viborg Hospital, Viborg, Denmark (J.R.); Dr. Arvo Rosenthal LLC, Estonia (A.R.); Azienda Ospedaliera
Papa Giovanni XXIII, Cardiologia 1 – Scompenso e Trapianti di Cuore, Bergamo, Italy (M.S.); St. Luke’s Heart Institute, Quezon City, Philippines (A.S.S.);
Center for Health Technology and Services Research (CINTESIS), Porto Medical School, University of Porto, Portugal (J.S.-C.); Department of Cardiovascular
30
zation
0
0
180
360
540
720
900
1080 1260 1440
Days After Randomization
Figure 2. Cumulative number of hospitalizations for heart failure
in the enalapril and LCZ696 groups per 100 patients. Shown is
Who should be treated with
sacubatril-valsartan?
• ARNI therapy (valsartan/sacubitril) is
recommended in patients with NYHA Class
II or III systolic congestive heart failure
who can tolerate an ACE inhibitor or ARB
as disease modifying therapy with:
• Elevated brain derived natriuretic peptide
> 150 pg/mL or NT-pro-BNP > 600 pg/mL
• Elevated brain derived natriuretic peptide
> 100 pg/mL or NT-pro-BNP > 400 pg/mL
WITH a prior hospitalization for congestive
heart failure in the past 12 months
Who should be treated with
sacubatril-valsartan?
• ARNI should not be administered with
ACE inhibitors or ARBs within 36 hours
of the last dosage.
• Valsartan/sacubitril is not intended for
subjects with low systolic blood
pressure < 100 mm Hg, eGFR < 30
mL/min/1.73m2, or potassium > 5.2
mmol/L.
• Hypotension and angioedema are
potential effects of the drug.