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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5212_Библиотеки_им_академика_М_И_Перельмана.pdf
Editor and Contributors
About the Editor
Jon Kobashigawa MD, is the DSL/Thomas D. Gordon professor of
Medicine, director of the Advanced Heart Disease Section, director of the
Heart Transplant Program and the associate director of the Cedars-Sinai
Smidt Heart Institute as well as the associate director of the Comprehensive
Transplant Center of the Cedars-Sinai Medical Center.
He received his undergraduate degree at Stanford University and earned his
medical degree at Mount Sinai School of Medicine in New York. He is a past
president of the International Society of Heart and Lung Transplantation, past
chair of the American College of Cardiology Committee on Heart Failure and
Transplantation, and past member of the United Network of Organ Sharing
National Thoracic Committee and President of the American Society of
Transplantation.
Dr. Kobashigawa is recognized nationally and internationally as a leader in
heart transplantation. He has published more than 400 peer-reviewed articles,
chapters and monographs in the field of heart failure and transplantation and
has chairedseveral multicenter clinical studies. Dr. Kobashigawa has organized and chaired numerous International Consensus Conferences to discuss
pertinent questions regarding heart failure and heart transplant. He lectures at
universities around the world and has mentored many young physicians who
have ascended to important academic positions throughout the country.
Contributors
Juan C. Alejos UCLA Mattel Children’s Hospital, Los Angeles, CA, USA
Yevgeniy Brailovsky Thomas Jefferson University, Philadelphia, PA, USA
Pedro Catarino Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA
David H. Chang Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA
xiii
xiv Editor and Contributors
Robert M. Cole Cedars-Sinai Smidt Heart Institute, Los Angeles, CA,
USA
Howard J. Eisen Thomas Jefferson University, Philadelphia, PA, USA
Fardad Esmailian Cedars-Sinai Smidt Heart Institute, Los Angeles, CA,
USA
Michele Hamilton Cedars-Sinai Smidt Heart Institute, Los Angeles, CA,
USA
Majid Husain UCLA Mattel Children’s Hospital, Los Angeles, CA, USA
Michelle M. Kittleson Cedars-Sinai Smidt Heart Institute, Los Angeles,
CA, USA
Jon Kobashigawa Cedars-Sinai Smidt Heart Institute, Los Angeles, CA,
USA
Evan Kransdorf Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA
Andrew Lin Aurora St. Luke’s Medical Center, Milwaukee, WI, USA
Yosef Manla Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA
Jaime D. Moriguchi Cedars-Sinai Smidt Heart Institute, Los Angeles, CA,
USA
Emily Newman Thomas Jefferson University, Philadelphia, PA, USA
Andriana P. Nikolova Cedars-Sinai Smidt Heart Institute, Los Angeles,
CA, USA
Jillian Oft Division of Infectious Diseases, Cedars-Sinai Medical Center,
Los Angeles, CA, USA
Jignesh Patel Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA
Krishan Patel Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA
Yael Peled Leviev Heart and Vascular Center, Sheba Medical Center, Tel
Hashomer, Ramat Gan, Israel; Faculty of Medical and Health Sciences, Tel
Aviv University, Tel Aviv, Israel
Indranee Rajapreyar Tufts Medical Center, Philadelphia, PA, USA
Lily Stern Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA
Rose Tompkins Cedars-Sinai Medical Center, Guerin Congenital Heart
Program, Smidt Heart Institute, Los Angeles, CA, USA
Phillip Zakowski Division of Infectious Diseases, Cedars-Sinai Medical
Center, Los Angeles, CA, USA
Xiaohai Zhang HLA and Immunogenetics Laboratory, Comprehensive
Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Part I
Advanced Heart Failure Treatments
Medical Therapy for Patients with End-Stage Heart Failure
Michele Hamilton and Yosef Manla
1
Abstract
Medical and device therapy for heart failure
(HF) has evolved substantially over the past
decade. This has changed the landscape not
only towards improved survival and quality
of life for all HF patients but also resulted in
more appropriate and efficient utilization of
advanced HF therapies, including heart transplantation and mechanical support in those
with end-stage HF. This chapter provides
a comprehensive guide to navigating the
evolving therapeutic options for HF patients,
focusing on the four pillars of guidelinedirected medical therapy for heart failure
with reduced ejection fraction. The chapter
also explores device therapies and highlights
the need for patient-centered care.
Keywords
Heart failure · Inotropes · Implantable
cardioverter-defibrillator · Cardiac
resynchronization
M. Hamilton (*) · Y. Manla
Cedars-Sinai Smidt Heart Institute, Los Angeles,
CA, USA
e-mail: michele.hamilton@cshs.org
Y. Manla
e-mail: Yosef.manla@cshs.org
Clinical Pearls
• For patients presenting with advanced HF,
whenever possible, the goal is to further optimize medical therapy and lifestyle opportunities, with ultimate referral for heart
transplantation or durable mechanical support
if the patient’s condition does not stabilize.
• Established “pillars” of guideline-directed
medical therapy (GDMT) include renin-angiotensin system (RAS) inhibitors, betablockers,
mineralocorticoid receptor antagonist (MRAs),
and sodium-glucose cotransporter 2 (SGLT-2)
inhibitors. These GDMTs have been demonstrated to reduce heart failure hospitalizations
and mortality. Systematic upward titration
to maximally tolerated doses of all of these
agents is key to improving patient outcomes.
• Diuretics continue to be central to reducing
congestion in patients with volume overload.
• Sacubitril/ valsartan (an angiotensin receptor and neprilysin inhibitor, ARNI) is indicated as the first-line RAS inhibitor therapy
for patients with class II/III heart failure,
with careful monitoring of renal function and
BP during titration. A 36-h wash-out period
is needed during any change to or from an
ACEI and ARNI.
• SGLT2 inhibitors are indicated for all
symptomatic heart failure patients, with or
without diabetes, across all left ventricular
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2025
J. Kobashigawa (ed.), Clinical Guide to Heart Transplantation, https://doi.org/10.1007/978-3-031-88290-6_1
3
4 M. Hamilton and Y. Manla
ejection fractions, as long as renal function
is not severely impaired (eGFR less than
20–30 ml/min).
• The implantable cardioverter-defibrillator
is a suitable option for primary prevention in patients with LVEF ≤ 30% at least
40 days after myocardial infarction, and in
patients with symptomatic ischemic and nonischemic heart failure (NYHA Class II-III,
LVEF < 35%) despite optimization of medical
therapy.
• Cardiac resynchronization therapy is also
appropriate for heart failure patients (NYHA
class II-ambulatory IV, LVEF ≤ 35%) who
demonstrate substantial prolongation of the
QRS interval on ECG (≥150 ms) and are in
sinus rhythm.
• Other medications, including vericiguat and
ivabradine, and interventions such as transcatheter mitral valve repair or implantable
pulmonary artery pressure sensors may also
be considered for patients with persistent HF
symptoms despite maximally tolerated GDMT.
• Type IC antiarrhythmics and dronedarone,
as well as the non-dihydropyridine calcium
channel blockers, diltiazem and verapamil,
and the diabetes medications (thiazolidinediones and DPP-4 inhibitors) are contraindicated in patients with HFrEF. NSAIDs may
also lead to worsening renal function and
fluid retention in this population.
Introduction
Heart Failure (HF) continues to impose a significant burden on patients and healthcare systems
worldwide. In the United States, HF prevalence
continues to rise, largely because of the increasing age of the population and improved postmyocardial infarction survival. In 2020, there
were over 6.7 million HF patients, leading to over
1 million hospitalizations. HF was a contributing
cause to at least 400,000 deaths [1, 2]. Multiple
classification systems have been developed to
precisely characterize the extent of disease progression in patients with HF patients, including the American College of Cardiology (ACC)/
American Heart Association stages of HF progression and the New York Heart Association
(NYHA) functional classification of HF symptoms and functional capacity [3, 4] (Table 1.1).
Medical and device therapy for HF has
evolved substantially over the past decade. This
has changed the landscape not only towards
improved survival and quality of life for all
HF patients but also resulted in more appropriate and efficient utilization of advanced HF
therapies, including heart transplantation and
mechanical support in those with end-stage HF
[3]. Unfortunately, significant racial and ethnic
disparities persist in both survival and access
to care, including access to advanced therapies, with non-Hispanic Black patients having
the highest mortality rate [5]. Somewhat counterintuitively, despite improvements in postmyocardial infarction survival and HF therapy,
demographic rise in overall life expectancies has
contributed to an actual increase in the advanced
HF population [6].
Most of the pharmacological therapies discussed below are usually initiated in patients in
the earlier stages of HF; however, in the evaluation of patients with advanced HF, we should
attempt to maximize any indicated medical
and device therapies to stabilize them, which
can potentially delay or avoid the need for
transplantation. Though approximately half of
HF patients have preserved systolic function
(HFpEF), those with reduced systolic function—
LVEF < 40% (HFrEF)—are generally younger
and have fewer comorbidities, comprising the
majority of those eligible for transplantation and
mechanical circulatory support; consequently,
the focus of this discussion will be on HFrEF
[3]. However, some patients with HFpEF,
including those with refractory arrhythmias or
ischemia and restrictive and hypertrophic cardiomyopathies, may also be appropriate transplant
candidates.
1 Medical Therapy for Patients with End-Stage Heart Failure
activity. Ordinary physical
activity does not cause
symptoms of HF
activity. Ordinary physical
activity does not cause
symptoms of HF
sical activity. Comforta-
ble at rest, but ordinary
physical activity results in
symptoms of HF
physical activity. Comfor-
table at rest, but less than
ordinary activity causes
symptoms of HF
physical activity without
symptoms of HF, or symp-
toms of HF at rest
physical activity without
symptoms of HF, or symp-
toms of HF at rest
5
–
I No limitation of physical
heart disease, or cardiac biomarkers of stretch or
injury
I No limitation of physical
of the following
– Structural heart disease
– Increased filling pressures or
– Risk factors and increased levels of biomarkers*
symptoms of HF
II Slight limitation of phy-
III Marked limitation of
IV Unable to carry on any
IV Unable to carry on any
life and with recurrent hospitalizations despite
attempts to optimize GDMT
ACC/AHA stages of HF [3] NYHA functional classification 2013 [4]
Stage A: at risk for HF At risk for HF but without symptoms, structural
Table 1.1 Comparison of classifications of heart failure disease progression and symptoms
Stage B: pre-HF No symptoms or signs of HF with evidence of 1
Stage C: symptomatic HF Structural heart disease with current or previous
Stage D: advanced HF Marked HF symptoms that interfere with daily
or Persistently elevated cardiac troponin in the absence of competing diagnoses resulting in such biomarker elevations
*
ACC, indicates American College of Cardiology; AHA, American Heart Association, GDMT, guideline-directed medical therapy; and HF, heart failure, NYHA: New York
Heart Association
6 M. Hamilton and Y. Manla
Medical Therapy for Heart Failure with Reduced Ejection Fraction HFrEF
The importance of a diligent approach to the
prevention of HF in Stage A (risk factors only)
and Stage B (structural cardiac disease without
HF) patients cannot be overemphasized [3].
For patients who have developed HF symptoms
(Stages C and D), our medical therapy has
evolved to include diuresis for congestive
symptoms and fluid retention, in conjunction
with four “pillars of therapy” with Level 1
indications, together referred to as “guidelinedirected medical therapy “(GDMT). These
include renin-angiotensin system inhibitors,
beta-blockers, mineralocorticoid inhibitors
(MRA), and, most recently, sodium-glucose
cotransporter-2 inhibitors (SGLT2i) (Fig. 1.1).
In addition, lifestyle changes, including
smoking cessation, avoidance of alcohol for
some patients, healthy diet, as well as increasing exercise and outpatient cardiac rehabilitation programs (Level 1A and 2A indications),
can contribute to improved survival, functional
capacity, and quality of life [3, 7–9].
One of the major interventions to improve
outcomes in HF patients is an emphasis on
maximizing the number and target doses of
the GDMT. The studies for each element of
our therapy have shown the greatest benefit for
those achieving target doses [10–22]. There
are also registry data demonstrating substantial improvement in outcomes for each additional element. Despite this information, only
approximately 40% of outpatients appear to
be on each of the appropriate medications, and
very few are on target doses of all medications
[23]. Though there are individual-specific contraindications to achieving some of these goals
(such as renal insufficiency and hypotension),
other barriers, such as high cost, poor access to
care, and incomplete medication education, need
to be addressed to maximize GDMT for all our
patients.
From a practical standpoint, in a stable,
chronic HF patient, a ladder-type approach
with alternating, steady upward titration of
each family of medications every 1–2 weeks,
with close monitoring of symptoms, vitals,
and laboratory studies, can efficiently
achieve the optimal regimen. A specialized,
multidisciplinary program may facilitate this
process for complex patients. Patients with
persistent symptoms with minimal activity
(NYHA Class III) or at rest (Class IV)
despite maximally tolerated GDMT or who
demonstrate progressive HF with worsening
end-organ damage or intolerance to prior
GDMT are classified as Stage D and often
labeled “advanced” or “end-stage.” Regardless
of etiology, stage D HF patients have a high
5-year mortality rate and warrant referral
to a specialized center. If the patient fails
Fig. 1.1 Treatment recommendations for patients with
HFrEF are displayed. Step 1 medications may be started
simultaneously at initial (low) doses recommended
for HFrEF. Alternatively, these medications may be
started sequentially, with sequence guided by clinical
or other factors, without need to achieve target dosing
before initiating next medication. Medication doses
should be increased to target as tolerated (Adapted
with permission from: Heidenreich et al. 2022). ACEi,
indicates angiotensin-converting enzyme inhibitor; ARB,
angiotensin receptor blocker; ARNi, angiotensin receptorneprilysin inhibitor; COR, Class of Recommendation;
CRT, cardiac resynchronization therapy; GDMT,
guideline-directed medical therapy; ICD, implantable
cardioverter-defibrillator; hydral-nitrates, hydralazine and
isosorbide dinitrate; HFrEF, heart failure with reduced
ejection fraction; LBBB, left bundle branch block; MCS,
mechanical circulatory support; LVEF, left ventricular
ejection fraction; MRA, mineralocorticoid receptor
antagonist; NSR, normal sinus rhythm; NYHA, New
York Heart Association; and SGLT2i, sodium-glucose
cotransporter 2 inhibitor. as a footnote or in a reference
list at the end of your publication, as follows. Reprinted
from Journal of the American College of Cardiology,
79 (17), Paul A. Heidenreich, Biykem Bozkurt, David
Aguilar, Larry A. Allen, Joni J. Byun, Monica M. Colvin,
Anita Deswal, Mark H. Drazner, Shannon M. Dunlay,
Linda R. Evers, James C. Fang, Savitri E. Fedson, Gregg
C. Fonarow, Salim S. Hayek, Adrian F. Hernandez et al.
2022 AHA/ACC/HFSA Guideline for the Management
of Heart Failure A Report of the American College of
Cardiology/American Heart Association Joint Committee
on Clinical Practice Guidelines, e263–e421. Copyright
(2020), with permission from Elsevier
▼
71 Medical Therapy for Patients with End-Stage Heart Failure
8 M. Hamilton and Y. Manla
oral medical therapy, the medical treatment
may shift to hemodynamically guided
therapy with an indwelling pulmonary artery
catheter and intravenous vasodilator and/
or inotropic agents or possible temporary
mechanical devices, in conjunction with
evaluation for cardiac transplantation and/
or durable mechanical support (see Chaps. 2
and 3). For patients not felt to be appropriate
candidates for advanced therapies, palliative
options, including home inotropic support or
hospice care, may be considered. Palliative
and supportive care discussions to assist with
symptom management, caregiver support, goals
of care, etc. should be incorporated throughout
the course of HF illness by all levels of care
providers [24].
Diuretics/Fluid Management
Diuretics, most commonly loop diuretics such
as furosemide, bumetinide, and torsemide, are
recommended across all HF populations with
symptoms and signs of fluid retention and are
integral to the care of advanced HF patients.
They have a Class 1 indication, with only level
of evidence C due to their importance for symptom management and improving exercise tolerance [3], but lack of data demonstrating survival
benefit. For patients with right ventricular failure
and presumed intraperitoneal fluid and bowel
edema, bumetanide and torsemide may have better relative absorption than furosemide. In cases
of treatment-refractory fluid overload, loop diuretic effect may be effectively “boosted” when
these diuretics are used in combination with a
thiazide such as metalazone [25]. In hospitalized
patients with refractory fluid overload and worsening hyponatremia, vasopressin antagonists
(tolvaptan) may be temporarily effective, but,
like the addition of a thiazide diuretic, they have
not proven to improve outcomes. Controversy
exists regarding the benefit of dietary salt and
fluid restriction [26]; in general, salt restriction
to less than 2–3 gm/day is felt to be prudent for
patients with congestive symptoms (Class 2A
recommendation), with fluid restriction reserved
for those with more refractory volume management issues [3].
Renin-Angiotensin Inhibitors: ACE Inhibitors (ACEi), Angiotensin Receptor Blockers (ARB), and Combined ARB/Neprilysin Inhibitors (ARNi)
Angiotensin-converting enzyme inhibitors
(ACEi) were considered the first-line treatment
for chronic symptomatic heart failure with
reduced ejection fraction (NYHA Class II/
III), based on studies demonstrating improved
survival [19], and ARBs remain a reasonable
alternative for ACEi intolerant patients (due
to cough or angioedema) [27]. However, the
development of the ARNis has changed this
paradigm. Sacubitril/valsartan is a combination
of a neprilysin inhibitor which reduces
breakdown of natriuretic peptides, and an ARB.
The sacubitril entity provides additional diuresis
and vasodilation (including in the pulmonary
circuit). PARADIGM-HF, a randomized trial
of sacubitril/valsartan compared to the ACEinhibitor, enalapril, in HFrEF, showed evidence
at 27 months of reduction in a combined
endpoint of HF admissions and mortality in the
sacubitril/valsartan study arm, with the primary
benefit related to reduced hospitalizations
[14]. Based on these data and studies showing
safety of initiating ARNIs in hospitalized and
ACEI -naïve patients [28], ARNIs are now
recommended as first line therapy for NYHA
Class II/III HFrEF patients (Class1A). It is
also recommended that patients on ACEi/
ARB should be switched to an ARNi when
possible, but there must be at least a 36-h
hiatus between doses for any change to/from
ARNi and ACEi due to angioedema risk. From
a practical standpoint, especially in advanced
HF patients, ARNIs may lead to a greater
drop in blood pressure due to the additional
91 Medical Therapy for Patients with End-Stage Heart Failure
diuretic and vasodilatory properties, so ACEis
and ARBs may be initiated instead in patients
with marginal initial blood pressures (less than
90–100 mmHg) or those previously intolerant
of an ARNI due to an unacceptable hypotensive
response. Blood pressure and renal function
must be monitored regularly for any of these
medications, and none of them should be used
concurrently. Notably, sacubitril/valsartan is
contraindicated in patients with any history of
angioedema or other adverse reactions to ACEi.
Beta-Blockers
In combination with ARNIs or ACE inhibitors, beta blockers should be prescribed to all
patients with stable heart failure (NYHA II–IV)
with reduced ejection fraction. Large, international multicenter trials demonstrated that
carvedilol, bisoprolol and metoprolol succinate
are effective in reducing the risk of death and
combined risk of death or hospitalizations [29].
The COPERNICUS trial specifically demonstrated their safety in the NYHA Class IV population [11]. Initiation of beta-blockers should
be avoided in patients with substantial volume
overload or on inotropic support within the
past 48 h, due to the potential for exacerbating
HF in those situations. Carvedilol is considered
the first-line betablocker due to an incremental
survival benefit over metoprolol in the COMET
trial [30]; however, metoprolol, a more cardioselective agent without additional alpha-blockade
properties, may be preferrable for patients with
relatively low blood pressure or a history of
bronchospasm. All betablockers need gradual
upward titration to monitor for bradycardia and
hypotension, and minimize worsening fatigue
symptoms.
Mineralocorticoid-Receptor Antagonists
Aldosterone-receptor antagonists, including
spironolactone and eplerenone, have survival
benefit in immediate post-MI patients with HF
and LVEF < 40% as well as NYHA Class II-IV
chronic HFrEF patients, when added to other
medical therapy [15, 31]. These agents have only
mild diuretic properties with potassium sparing, but their survival benefit is felt to be related
to avoidance of adverse remodeling. Renal function must be monitored closely upon initiation
and upward titration of MRAs, with concomitant reduction in replacement potassium dosing. MRAs should be avoided in patients with
renal insufficiency (eGFR less than 30 mL/
min/1.73m2) and hyperkalemia (>5.0 mEq/dl).
Patients should also be advised of the approximately 10% risk of breast tenderness and/or
gynecomastia.
SGLT2 Inhibitors
SGLT2i’s inhibit glucose reabsorption in the
kidney and are known to reduce HF admissions
in diabetic patients with cardiovascular disease
(or at high risk). More recently, multiple trials,
including DAPA-HF and EMPEROR-Reduced,
have consistently shown reduction in a combined endpoint of HF admissions and mortality
(related primarily to HF hospitalizations) from
SGLT2i in symptomatic HF patients, in diabetics and non-diabetics, and across all LVEF
groups [32, 33]. Diuretic dosing should usually
be reduced and renal function monitored closely
when SGLT2i are initiated due to the glucosuriarelated diuresis caused by these medications.
They should be avoided in patients with eGFR
less than 20–30 mL/cc/min/1.73 m2.They often
lead to a small rise in creatinine when initiated, but actually provide renal protection over
1 year follow up (34). Hypotension, euglycemic ketoacidosis, and peroneal infections are
additional potential risks, but overall consideration has led to a Class 1A indication for the
addition of SGLT2i to the other GDMT in all
symptomatic HF patients. Thiazolidinediones
and DPP-4 inhibitors should be avoided in HF
patients [3].