Abstract
Cardiotoxicity is the most dramatic complications of cancer therapies,
leading to halt in potentially life-saving anti-tumor treatment regimens
and a poor survival prognosis in a non-negligible percentage of
patients. Angiotensin converting enzyme inhibitors (ACEIs) and
β-blockers are effective in the treatment of the cancer therapy–related
cardiac dysfunction (CTRCD), while their roles in the prevention of
cardiotoxicity are unclear. Sacubitril/valsartan was advantageous over
ACEI in heart failure patients for further reduction of cardiovascular
death or heart failure re-hospitalization. However, there is short of
well-established testimony of its efficacy and safety in the prevention
and treatment of CTRCD in the cardio-oncology setting. Although some
small observational studies found a good performance of
sacubitril/valsartan in patients with CTRCD, large-scale prospective
clinical studies are required to confirm its excellent results. In this
paper, we review the potential benefit of sacubitril/valsartan in human
subjects with CTRCD.
Keywords: Cardio-oncology; Cancer therapy–related cardiac
dysfunction; Cardiotoxicity; Angiotensin receptor-neprilysin inhibitor;
Sacubitril/valsartan
Background and epidemiology
Malignant tumors and cardiovascular diseases (CVDs) represent the two
main causes of death in the world (1). Both conditions mutually
influence each other in pathophysiology (2). Meanwhile, CVDs and tumors
hold numerous shared risk factors such as aging, smoking, infections,
diet, alcohol, obesity and physical inactivity (1). Therapeutic Advances
in cancer has led to an increased prevalence of cancer therapy–related
cardiac dysfunction (CTRCD) commonly defined as an absolute reduction in
left ventricular ejection fraction (LVEF) of ≥10% or reduction in LVEF
to <50% (3).
The SEER database found that cardiovascular event is a major cause of
death among cancer survivors (4). Cardiovascular complications of cancer
treatment, especially cardiomyopathy and heart failure, lead to the
discontinuity of therapeutic regimens and affect the survival prognosis
of patients (5). Considering that state of the art in oncology
therapeutics and aged tendency of population, establishing a unified
framework for the management of CTRCD is required to reduce the risk of
cardiac death among cancer survivors (3).
Cardio-oncology aims to address the spectrum of prevention, early
diagnosis, monitoring, and timely treatment of CTRCD among cancer
survivors (3, 6). However, CTRCD is a heterogeneous condition, with all
kinds of clinical presentation from pre-clinic systolic dysfunction to
cardiac shock (7). Heart failure secondary to CTRCD is associated with
significantly worse outcomes (8).
Cardiotoxicity was further heightened after trastuzumab administered
with anthracyclines simultaneously or sequentially. Among 12,500
patients with breast cancer, cumulative rates of CTRCD at the first and
five year were 1.2% and 4.3% in patients using anthracycline alone,
compared to 6.2% and 20.1% in patients receiving a combination
regimens of anthracyclines and trastuzumab (9). A retrospective study
from Thailand also found a higher risk profile in CTRCD among breast
cancer patients treated with a combination of anthracycline and
trastuzumab (10). Cardiac dysfunction induced by anthracyclines was
usually irreversible, with significant myocardial ultrastructural
abnormalities where oxidative stress damage was considered to be the key
mechanism for inducing cardiotoxicity (3). In sufferers progressing
anthracycline-induced cardiomyopathy, the recovery of cardiac function
was promoted and implemented when CTRCD was diagnosed early and treated
timely and promptly (11). One study of anthracycline-induced heart
failure showed a 64% response rate when administered within one to two
months of discovery of myocardial toxicity, compared to zero response
rate when treatment was reinitiated six months later (11).
Monoclonal antibodies including trastuzumab and pertuzumab formed the
backbone of therapeutic means in HER2-positive breast cancer. The
incidence of severe CTRCD [New York Heart Association (NYHA) class III
or IV] was 0-3.9% in the trastuzumab group versus 0-1.3% in the
control group in a meta-analysis with five randomized adjuvant trials
(12). A retrospective cohort study included 386 breast cancer patients
from Taiwan found that trastuzumab therapy increased the risk of major
adverse cardiovascular events, especially in heart failure (13).
Trastuzumab therapy–induced cardiomyopathy differed from
anthracyclines-related cardiotoxicity where it appeared to be reversible
in some degree, independent of the cumulative dose, and the second
exposure was usually tolerated (12). A meta-analysis of eight randomized
controlled trials where the gain of pertuzumab to standard care in
HER2-positive cancer patients was to determine the risk of cardiac
adverse events (14). Pertuzumab increased the risk profile in
symptomatic heart failure, but not silent cardiac insufficiency (14).
Besides, immuno-checkpoint inhibitors (ICIs)-induced
myocarditis/pericarditis is severe and usually associated with high
mortality although rare incidence (15).
Prevention and treatment of CTRCD
Patients who developed CTRCD should have these therapies discontinued
while multidisciplinary consultation should be launched to ascertain the
cause of heart failure and assess that whether or when cancer treatment
needs to be initiated again (7). The comprehensive decision-making to
resume, modify, or permanently discontinue therapy should be done in a
patient-centered approach (7). Essentials influencing the policymaking
included the disease severity of CTRCD and the response to
neuroendocrine inhibitor, the offending agent’s underlining
pathophysiology to myocardial damage, the comorbidity and tumor
prognosis (7).
Anthracycline and trastuzumab-induced cardiotoxicity could lead to the
interruption or cessation of life-saving cancer therapies. Available
data in patients with CTRCD suggest β-blockers and angiotensin
converting enzyme inhibitors (ACEIs) were medicative in improving
cardiac function (8, 11, 16). In a heterogeneous cohort of 2,625
patients receiving anthracyclines for breast cancer or lymphoma, CTRCD
occurred in 9% of patients and was related to anthracycline accumulated
dose, of whom 81% had mild cardiac dysfunction (16). Early detection
and prompt therapy with β-blockers and ACEI/angiotensin receptor
blockers (ARB) critically contributes to recovery of cardiac function
(16).
Whether the prophylactic use of β-blockers, spironolactone or ACEI/ARB
is protective against CTRCD in patients without established cardiac
disease has been investigated in some small clinical trials, with
contradictory results (17-24). Of the 473 cancer patients, 114 patients
who showed an elevated troponin I greater than 0.07 ng/ml after
high-dose chemotherapy were randomly assigned to ACEI or placebo (19).
The incidence of CTRCD was obviously higher in control subjects compared
to the enalapril group (43% versus 0%) (19). Evident declines of LVEF
and increased LV volumes were discovered only in the standard of care
arm. Early management with ACEI might prevent the progression of late
cardiotoxicity (19). In 468 patients with HER2-positive breast cancer
treated with trastuzumab, both lisinopril and carvedilol prevented
cardiotoxicity in patients receiving anthracyclines (20). Spironolactone
used in female patients diagnosed with breast cancer protected against
anthracycline-induced cardiotoxicity (17). A meta-analysis of five
randomized trials evaluated the prophylactic effect of β-blockers or
ACEIs/ARBs on reducing the incidence of CTRCD in breast cancer patients
receiving a trastuzumab regimen (21). Prophylactic treatment with
β-blockers or ACEIs/ARBs did not reduce the risk of CTRCD but did reduce
the risk of HER2 therapy interruptions and reduced LVEF (21).
Other researches have presented comparable results, but the scale of
change in LVEF between groups was usual minor (<5%) and short
of clinical implication (18). Furthermore, not all researches have
replicated such results (22, 23). A prospective, randomized,
double-blind, placebo-controlled study found that carvedilol had no
impact on the incidence of early onset of LVEF reduction (22). However,
the use of carvedilol resulted in a significant reduction in troponin
levels and diastolic dysfunction (22). Although perindopril and
bisoprolol protected against trastuzumab-mediated declines in LVEF in
patients with HER2-positive early breast cancer, left ventricular
remodeling was not prevented by these pharmacotherapies (24). No studies
have evaluated whether prophylactic use of neuroendocrine inhibitors in
subjects at risk for CTRCD improved clinical outcomes, such as mortality
or hospitalization for heart failure (7).
Sacubitril/valsartan
The introduction of angiotensin receptor-neprilysin inhibitor (ARNI) had
a revolutionary therapeutic effect in patients with heart failure and
reduced ejection fraction (HFrEF). Sacubitril/valsartan has a distinct
dual neuroendocrine regulation mechanism. Sacubitril enhanced
natriuretic peptides’ levels through inhibiting neprilysin by its
metabolite LBQ657, while valsartan inhibits the
renin-angiotensin-aldosterone system (RAAS) through blocking angiotensin
II type 1 (AT1) receptors (25). Sacubitril/valsartan was advantageous
over ACEI in heart failure patients for further reduction of
cardiovascular death or heart failure hospitalization (26). In the
PIONEER-HF trial, among stabilized patients with HFrEF who were
hospitalized for acute decompensated heart failure, the initiation of
sacubitril/valsartan therapy was well tolerated and led to a greater
decline in the level of N-terminal pro-B-type natriuretic peptide
(NT-proBNP) compared to ACEI did (27). Switching treatment from ACEI to
sacubitril/valsartan at 8 weeks resulted in a 37% reduction in
NT-proBNP concentration during an open-label extension phase of the
PIONEER-HF trial (28). Patients who began taking sacubitril/valsartan in
hospital had a lower risk profile for heart failure re-hospitalization
and cardiovascular death than patients with a delayed initiation of
sacubitril/valsartan (8 weeks later) (28).
LV remodelling was crucial in progression to HFrEF (29). The extent of
improvement in LV volumes, dimensions, and LVEF after therapy strongly
correlated with clinical outcomes, including survival (30). LV
remodelling was realized after administration of with
sacubitril/valsartan in clinical scenarios (31). A smaller LV capacity
was relevant to preferable LV reverse remodelling (31). Therefore,
sacubitril/valsartan is the optimal recommendation for the the
management of chronic HFrEF patients (7).
Sacubitril/valsartan in CTRCD
To my knowledge, data about the efficacy of sacubitril/valsartan on
CTRCD are scarce. Although cancer patients were not excluded ”a priori”
from enrollment in the pivotal PARADIGM-HF trial, which could be
enrolled after 12 or more months from cardiac toxicity, but
investigators ultimately decided not to enroll (26). Most observational
researches showed that sacubitril/valsartan improved the cardiac
structure and function as well as NT-proBNP levels in patients with
CTRCD (32).