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Eduvest � Journal
of Universal Studies Volume 1 Number 8, August 2021 p- ISSN
2775-3735 e-ISSN 2775-3727 |
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BAROREFLEX ACTIVATION THERAPY (BAT)
EFFECTIVENESS AMONG HEART FAILURE PATIENTS: A SYSTEMATIC REVIEW AND
META-ANALYSIS |
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Farahdina
Farahdina, Muhammad Ilham Hernawan, Wiryantari Akhdani Pratiwi,
Hapsary Puteri Widodo, Vatine Adila Brawijaya
University, Airlangga University E-mail: [email protected], [email protected], [email protected], [email protected],
[email protected] |
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ARTICLE
INFO������� ABSTRACT |
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Received: July,
24th 2021 Revised: August,
14th 2021 Approved: August,
16th 2021 |
Heart
failure is promoted by the imbalance of sympathovagal,
which increased sympathetic and decreased parasympathetic activity. BAT, an
electrical stimulation technology, cause the baroreflex
to be activated and balances the sympathovagal.
Systematic review and meta-analysis were conducted, including published
reports about the effectiveness of BAT in heart failure patients from PubMed,
Embase, Cochrane, and Google Scholar to calculate
the pooled standard mean difference and 95% confidence interval (95% CI)
using either random or fixed effect model. Our search strategy identified 161
possible studies. Thirteen studies have been included as a full-text review.
We excluded seven of these papers due to review, and our analysis has
included six papers. Our combined analysis has shown that BAT is associated
with an improvement in NYHA class compared to control (0.19[95%CI:
0.11-0.31], p = 0.000). Our pooled analysis also found that BAT, compared to
control, was associated with 6-MHWD improvement, (-136.25[95%CI: -181.34 -
-91.17], p = 0.000). Our pooled analysis also found that BAT, compared to
control, was associated with HF hospitalization (-6.38[95%CI: -8.46 - -4.30],
p = 0.000). BAT has a significant effect on improving NYHA Class, 6-minute
hall walk distance, and decreasing HF patient's hospitalization days.
Meanwhile, there is an insignificancy on LVEF and QoL
improvement in HF patients. Future studies are still needed. |
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KEYWORDS |
BAT, baroreflex,
HF, NYHA, LVEF |
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This
work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International
License |
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INTRODUCTION
Heart failure (HF) is
a complex clinical syndrome, with the character of the heart�s reduced ability
to pump and/or fill with blood. Physiologically, heart failure can be defined as
an inadequate cardiac output to meet metabolic demands or adequate cardiac
output secondary to compensatory neurohormonal
activation (Savarese & Lund, 2017). HF affect 26 million people worldwide. In 2012, HF was responsible for
an estimated health expenditure of around $31 billion, or more than 10% of the total health
expenditure for cardiovascular diseases in the United States (Mozaffarian et al., 2016). It is
estimated that the total cost expected to increase by 127% between 2012 and
2030. In Indonesia, heart failure had become the most leading cause for
hospitalization beside acute coronary syndrome (ACS) with high mortality and
readmission rate (Siswanto, 2013).
One of the therapies that has shown in the preliminary
study of heart failure is Baroreceptor Activation Therapy (BAT). BAT is an
electrical stimulation technology that causes the baroreflex
to be activated, decreases the activity of the sympathetic nerves, and
increased the parasympathetic activity by stimulating the carotid sinus using an
implanted device resembling a cardiac pacemaker. This stimulation results in
increased arterial and venous compliance and reduced peripheral resistance. By
doing so, BAT can improve the clinical status of a patient with HF (Abraham et al., 2015; Gronda et al., 2014; Zile, Abraham, Weaver,
Butter, Ducharme, Halbach, Klug, Lovett, M�ller-Ehmsen, et al., 2015).
Our present study aimed to perform a meta-analysis
regarding the baroreceptor activation therapy in heart failure with reduced
ejection fraction and the outcome to assess the baroreceptor activation
therapy's efficacy. Based on the evidence-based, we hypothesized that
Baroreceptor Activation Therapy (BAT) associated with improvement of Quality of
Life (QoL) score, NYHA Class, LVEF, 6-Minute Hall
Walk Distance (6-MHWD), and decreased the hospitalization rate and the average
number of days hospitalization.
RESEARCH METHODS
This systematic review and meta-analysis were conducted
from August to September 2020 to determine the effectiveness of Baroreflex Activation Therapy (BAT) in heart failure. Published
reported from PubMed, Embase, Cochrane, and Google
Scholar were conducted to calculate the pooled standard mean difference and 95%
confidence interval (95% CI) using either random or fixed effect model. The
current study has applied to ensure that our procedures, including record
collection, extraction of data, quality evaluation, and statistical analysis,
adhere to the PRISMA guideline from Preferred Reporting Items for Systematic
Examination and Meta-Analysis (PRISMA).
Several scientific references (PubMed, Embase, Cochrane, and Google Scholar) were searched for
studies assessing Baroreflex Activation Therapy
(BAT)�s efficacy in heart failure patients until September 15, 2020. We
restricted the publishing language. We did not include these characteristics in
our study if published papers were not found in both English and Indonesia. In
addition, the following keywords were used to perform a systemic search:
["Heart Failure" or "CHF" or "Congestive Heart
Failure"] and ["Baroreflex Activation
Therapy" or "BAT"] and ["Efficacy"]. If we found
documents with the same study details, we included only documents with larger
samples in our search strategy. Additionally, the following information of
interest was extracted from each paper: (1) first author name, (2) year of
publication, (3) sample size of case and control, (4) age of participants, (5)
ethnicity, (6) main findings, (7) Quality of Life score of case and control,
(8) NYHA class of case and control, (9) 6-Minute Hall Walk Distance (6MHWD) of
case and control, (10) Left Ventricular Ejection Fraction (LVEF), and
(10) the hospitalization of heart failure patients of case and control. To
provide high-validity data, two independent authors performed data extraction
to avoid human error (FF, WAP). If a discrepancy was found, we performed a
discussion with other authors (MIH, HPW).
The articles in our analysis were based on the
following criteria: (1) assessing the effectiveness of Baroreflex
Activation Therapy (BAT) in treating heart failure patients; and (2) having
required data for calculation of standard mean difference and 95% CI.
Furthermore, the criteria of exclusion were as follows: (1) unrelated titles
and abstracts, (2) reviews, (3) incomplete and or ungeneralized
data, and (4) have a deviation from Hardy-Weinberg equilibrium (X2 > 3.84
was defined as deviation from Hardy-Weinberg equilibrium).
Our present study's predictor covariate was Baroreflex Activation Therapy (BAT) effectiveness in
treating heart failure patients.� The
outcome parameters were the QoL score, NYHA class,
6-Minute Hall Walk Distance (6-MHWD), Left Ventricular Ejection Fraction (LVEF),
and heart failure hospitalization. They were determined after we performed
initial searching for covariates screening to include in our meta-analysis
calculation.
Prior to the meta-analysis, the quality measured every
paper using the scale of New Castle-Ottawa (NOS) �(Bae, 2016). The NOS score ranged from 0 to 9 and had three points:
patient selection (4 points), group comparability (2 points), and exposure
measurement (3 points). The paper was interpreted to be of low quality (for
scores 4), of moderate rate (for scores 5-6), and of high quality (for scores
7). Low-quality papers have not been included in our study. Two independent
investigators (FF and MIH) carried out the NOS assessment, who discussed with
the others (HPW, WAP) where there was a discrepancy.
The correlation and effect estimates of Baroreflex Activation Therapy (BAT) on heart failure
patients with the QoL score, NYHA class, 6-Minute Hall Walk Distance (6MHWD), Left Ventricular
Ejection Fraction (LVEF), and heart failure hospitalization were
assessed using a Z test. Data for heterogeneity and potential publication bias
were assessed before the significant factors were identified. The heterogeneity
was evaluated with the Q test. In the case of heterogeneity (p<0,10), a random effect model has been adopted, or a fixed
effect model has been applied. To determine reporting and publishing errors,
the Egger and funnel plot test (p<0.05 was considered publication bias). The
correlation and impact assessments were then presented using the forest plot.
Review Manager 5.4 (Revman Cochrane, London, UK) and
Comprehensive Meta-Analysis software (version 3.3.070, Biostat
Inc., Englewood, NJ, USA) were used to analyze the data. Two independent
authors (FF and MIH) performed statistical analyses in order to avoid
methodological errors.
RESULTS AND DISCUSSION
A. Eligible studies
Our search strategy
identified 161 possible studies. One hundred forty-eight of them were excluded
on the basis of titles and abstracts, which did not concern them. A total of 13
studies have been included as a full-text review. We excluded seven of these
papers due to review (n = 3), incomplete (n = 2) and poor quality (n = 2) data.
Finally, our analysis has included six papers. The paper selection route in our
study is summarized in Figure 1, and the baseline characteristics of the papers
included in our meta-analysis are described in Table 1.
Figure 1. A
flowchart of study selection in our study
Table 1. Baseline characteristics of articles
included in our study
|
Author & year |
Sample size |
Case setting |
Age (years) |
Ethnicity |
NOS |
Main findings |
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CON |
BAT |
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Abraham
et al., 2015 |
54 |
64 |
HF NYHA class III |
65 � 12 |
Caucasian |
7 |
BAT is tolerable
and improves functional status, quality of life, and hospitalizations in HF
NYHA class III patients (Abraham et al., 2015). |
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Dell-oro et al.,
2017 |
17 |
7 |
HF NYHA class III |
67 �� 3 |
Caucasian |
7 |
This study
provides evidence that BAT in heart failure with reduced ejection fraction
allows not only to improve hemodynamic and clinical profile but also to allow
an almost complete restoration of the sympathetic neural function's
physiological levels (Dell�Oro et al., 2017). |
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Gronda
et al., 2014 |
11 |
11 |
HF NYHA class III |
67 � 9 |
Caucasian |
7 |
BAT was safe and
provided a long term improvement in MSNA and clinical variables. Based on the
present understanding of HF pathophysiology, these results suggest that BAT may
improve outcomes in HF by modulating autonomic balance.(Gronda et al., 2014) |
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Gronda
et al., 2016 |
9 |
9 |
HF NYHA class III |
67 � 10 |
Caucasian |
7 |
This study showed
that BAT significantly reduced MSNA and has clinical improvement, but does
not appear to modify arterial stiffness within this HFrEF cohort chronically (Gronda et al., 2016). |
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Halbach
et al., 2018 |
36 |
47 |
HF NYHA class III |
- |
Caucasian |
6 |
No significant
differences were found in BAT efficacy or safety between patients with and
without CAD, indicating that BAT improves exercise capacity, quality of life,
and NTproBNP in patients with ischemic and nonischemic cardiomyopathy (Halbach et al., 2018). |
|
Zile et al., 2015 |
48 |
47 |
HF NYHA class III |
63 � 12 |
Caucasian |
8 |
BAT is tolerable
and significantly improved QoL, exercise capacity, NTpro-BNP, EF, and HF
hospitalizations rate in treated NYHA Class III HF patients (Zile, Abraham, Weaver,
Butter, Ducharme, Halbach, Klug, Lovett, M�ller‐Ehmsen, et al., 2015). |
Note,
NOS, Newcastle-ottawa scale; HF, Heart Failure; NYHA, New York Heart
Association; CON, Control; BAT, Baroreflex Activation Therapy
B. Data synthesis
We included six papers
evaluating the association between Baroreflex
Activation Therapy (BAT) and QoL score, five papers
evaluating the correlation between Baroreflex
Activation Therapy (BAT) and NYHA class improvement, six papers evaluating the
association of Baroreflex Activation Therapy (BAT)
and 6-MHWD, six papers evaluating the relationship between Baroreflex
Activation Therapy (BAT) and LVEF, and four papers evaluating the relationship
between Baroreflex Activation Therapy (BAT) and HF hospitalization.
Our combined analysis has shown that Baroreflex
Activation Therapy (BAT) is associated with an improvement in NYHA class
compared to control (OR: 0.19 [95%CI: 0.11-0.31], p = 0.000). Our pooled
analysis also found that Baroreflex Activation
Therapy (BAT), compared to control, was associated with 6-MHWD improvement,
(mean diff: -136.25 [95%CI: -181.34 - -91.17], p = 0.000). Our pooled analysis
also found that Baroreflex Activation Therapy (BAT),
compared to control, was associated with HF hospitalization, (mean diff: -6.38
[95%CI: -8.46 - -4.30], p = 0.000). However, QoL
score (mean diff: -16.46 [95%CI: -40.30 - 7.38], p = 0.18) and LVEF (mean diff:
-7.49 [95%CI: -12.59 - 2.39], p = 0.004) were not affected significantly
between Baroreflex Activation Therapy (BAT), and
control group. The summary of the correlation and effect estimates between Baroreflex Activation Therapy (BAT) and outcome measures in
our present study is outlined in Table 2 and Figure 2.
Table 2. Summary of
the association between Baroreflex Activation Therapy and Outcome Parameters
among Heart Failure Patients in our study
|
Outcome parameters |
NS |
Model |
Outcome measure |
Mean difference / OR |
95%CI |
pE |
pHet |
p |
|
|
|
|||||||||
|
Control |
BAT |
||||||||
|
QoL score |
5 |
Random |
11.2 � 13.8 |
-3 � 5 |
-16.46 |
-40.30 - 7.38 |
5.274 |
0.000 |
0.18 |
|
NYHA class improvement |
5 |
Fixed |
22% |
60% |
0.19 |
0.11-0.31 |
0.444 |
0.219 |
0.000 |
|
6-MHWD |
6 |
Random |
189 � 27.5 |
325 � 28.5 |
-136.25 |
-181.34 - -91.17 |
3.183 |
0.000 |
0.000 |
Note, data were presented in
mean � SD; NS, number of study; QoL, quality of life;
NYHA, New York Heart Association; MHWD, minute hall walk distance; LVEF, left
ventricular ejection fraction; CI, confidence interval; pE,
p Egger; pHet, p Heterogeneity.
C. Source of heterogeneity
Heterogeneity among studies
The evidence for
heterogeneity in the following covariates has been identified in our study: QoL score, 6-Minute Hall Walk Distance (6MHWD), Left
Ventricular Ejection Fraction (LVEF), and heart failure hospitalization.
Therefore, random effect model was used to assess the association between Baroreflex Activation Therapy (BAT) and the QoL score, 6-Minute Hall Walk Distance (6MHWD), Left
Ventricular Ejection Fraction (LVEF), and heart failure hospitalization.
In comparison, NYHA class covariate, we find no heterogeneity. Therefore, the
associations between Baroreflex Activation Therapy
(BAT) and NYHA class were tested using a fixed-effect model. Table 2 explains
the proof of heterogeneity between studies in our present meta-analysis.
Potential publication bias
We used the Egger test to
assess the possible differences between studies. Overall, our studies did not
contain any publication bias. Table 2 explains the description of the
discrimination to publications.
D. Discussion
Overall studies showed significant effects of
Baroreflex Activation Therapy (BAT) in improvement of NYHA Class and 6-minute
hall walk distance (6-MHWD) and decreased hospitalization days for Heart Failure patients. But there is insignificancy of
Baroreceptor Activation Therapy efficacy towards LVEF and QoL improvement. Five of six studies showed that Baroreflex
Activation Therapy (BAT) effectively improves NYHA class among heart failure
patients. On the other hand, another study could not validate their efficacy in
improving the NYHA class among HF patients. Moreover, six studies showed that Baroreflex Activation Therapy (BAT) effectively improves
6-MHWD among HF patients. Our pooled analysis revealed that the improvement of
NYHA class and 6-MHWD were observed in patients given Baroreflex
Activation Therapy (BAT) compared to heart failure patients without Baroreflex Activation Therapy (BAT). This study has never
been reported before, but only one systematic review reported it. Our findings
were consistent with the previous review. They also found that Baroreflex Activation Therapy (BAT) effectively improve
NYHA class and 6-MHWD among heart failure patients (Schmidt, Rodrigues,
Schmidt, & Irigoyen, 2020). Furthermore, in other settings, a meta-analysis was
performed to identified the correlation of Baroreflex Activation Therapy (BAT) and reduced of blood
pressure. Yet they revealed that Baroreflex
Activation Therapy (BAT) effectively reduced blood pressure in chronic heart
failure patients (Wallbach et al., 2016). This study makes us think that Baroreflex
Activation Therapy (BAT) may also be effective for heart failure patients in
other factors. However, theoretically, decreased baroreceptor sensitivity and increased
arterial stiffness are associated with increased sympathetic nerves that may
increase peripheral vascular resistance, which can decrease ejection fraction
and therefore decrease exercise capacity. Thus, baroreceptor activation therapy
may reduce this sympathetic activation, coupled with an increase in parasympathetic
activity (Abraham et al., 2015). This explanation might be underlying factors that Baroreflex Activation Therapy (BAT) improves HF patients' functional status as assessed
by NYHA Class improvement and 6-MHWD.
Besides NYHA class and
6-MHWD related to BAT revealed to have significant effects among HF patients,
HF hospitalization also had significant improvement on BAT patients. Four of
the six studies were analyzed and showed that Baroreflex
Activation Therapy (BAT) significantly improved
hospitalizations among heart failure patients. This result is consistent with
the previous review. They revealed that BAT lower hospitalization rates and the
number of days hospitalization after treatment (Schmidt et al., 2020). In other meta-analysis settings, there was no explanation
about the hospitalization effect after BAT because they just explain its impact
on reduced blood pressure among chronic heart failure patients (Wallbach et al., 2016). However, theoretically, increased sympathetic activity and decreased
parasympathetic activity occur as compensatory mechanisms in heart failure. But
in a long time, it can worsen heart failure. Baroreflex
activation therapy (BAT) produces centrally mediated sympathetic outflow and
increases parasympathetic activity. So, heart failure
progression may be reduced and reduced the HF hospitalization rate and the
average number of days hospitalization. The decrease of muscle sympathetic nerve activity
(MSNA) directly measured in the peroneal nerve via the microneurographic
technique was correlated to the reduction of HF hospitalization rate, which
also improved clinical status (Gronda
et al., 2014). This explanation might be underlying factors that Baroreflex Activation Therapy (BAT) reduced HF hospitalization
rate and the average number of days hospitalization.
A total of two parameters
were insignificant in our analysis. That two were the QoL
score and LVEF reduction. BAT's pathophysiology in failed to improve LVEF is
still unclear, may be due to the contribution of decreased sympathetic nerve
activity associated with BAT, which also reduces the contractility of the heart
muscle and makes the ejection fraction still consist the same and not
significantly improve (Abraham et al., 2015). The QoL score may have
many contributing factors, such as the limitation of sample study size, cofounding
factors, comorbid diseases, lifestyle,
gender, and medication adherence
that interfered with the patient's QoL score.
E.
Clinical
Implication
Despite the fact that we provided the evidence of
BAT efficacy as a treatment for HF patients in the term of NYHA class, 6-MHWD, and rate and an average number of
hospitalization, however, we
believed that there is a possibility
that BAT can improve LVEF and QoL, but,
because our data have limitation sample population, the further studies with a
higher population may be required. The use of BAT in addition to GDMT can be considered
because it has better results than GDMT alone.
CONCLUSION
Our study reveals that Baroreflex
Activation Therapy (BAT) has a significant effect on improving NYHA Class,
6-minute hall walk distance and decreasing hospitalization days for HF
patients. On the other side, there is an insignificancy effect on LVEF and QoL improvement in HF patients. Our study is the first
review with meta-analysis to conclude BAT's efficacy in treating HF patients.
Whether in the bigger sample size and heterogeneity across the included
literature, BAT correlates with LVEF, and QoL
improvement remains to be clarified by future studies.
REFERENCES
Abraham, William T., Zile, Michael R., Weaver, Fred A., Butter, Christian,
Ducharme, Anique, Halbach, Marcel, Klug, Didier, Lovett, Eric G.,
M�ller-Ehmsen, Jochen, & Schafer, Jill E. (2015).
Baroreflex activation therapy for the treatment of heart failure with a reduced
ejection fraction. JACC: Heart Failure, 3(6), 487�496.
Bae, Jong Myon. (2016). A suggestion for quality assessment in systematic
reviews of observational studies in nutritional epidemiology. Epidemiology
and Health, 38.
Dell�Oro, Raffaella, Gronda, Edoardo, Seravalle, Gino, Costantino, Giuseppe,
Alberti, Luca, Baronio, Barbara, Staine, Tiziana, Vanoli, Emilio, Mancia,
Giuseppe, & Grassi, Guido. (2017). Restoration
of normal sympathetic neural function in heart failure following baroreflex
activation therapy: final 43-month study report. Journal of Hypertension,
35(12), 2532.
Gronda, Edoardo, Brambilla, GianMaria, Seravalle,
Gino, Maloberti, Alessandro, Cairo, Matteo, Costantino, Giuseppe, Lovett, Eric,
Vanoli, Emilio, Mancia, Giuseppe, & Grassi, Guido. (2016). Effects of chronic
carotid baroreceptor activation on arterial stiffness in severe heart failure. Clinical
Research in Cardiology, 105(10), 838�846.
Gronda, Edoardo, Seravalle, Gino, Brambilla, Gianmaria, Costantino, Giuseppe,
Casini, Andrea, Alsheraei, Ali, Lovett, Eric G., Mancia, Giuseppe, &
Grassi, Guido. (2014). Chronic baroreflex
activation effects on sympathetic nerve traffic, baroreflex function, and
cardiac haemodynamics in heart failure: a proof‐of‐concept study. European
Journal of Heart Failure, 16(9), 977�983.
Halbach, Marcel, Abraham, William T., Butter, Christian, Ducharme, Anique, Klug,
Didier, Little, William C., Reuter, Hannes, Schafer, Jill E., Senni, Michele,
& Swarup, Vijay. (2018). Baroreflex
activation therapy for the treatment of heart failure with reduced ejection
fraction in patients with and without coronary artery disease. International
Journal of Cardiology, 266, 187�192.
Mozaffarian, Dariush, Benjamin, Emelia J., Go, Alan S., Arnett, Donna
K., Blaha, Michael J., Cushman, Mary, Das, Sandeep R., Ferranti, Sarah De,
Despr�s, Jean Pierre, Fullerton, Heather J., Howard, Virginia J., Huffman, Mark
D., Isasi, Carmen R., Jim�nez, Monik C., Judd, Suzanne E., Kissela, Brett M.,
Lichtman, Judith H., Lisabeth, Lynda D., Liu, Simin, MacKey, Rachel H., Magid,
David J., McGuire, Darren K., Mohler, Emile R., Moy, Claudia S., Muntner, Paul,
Mussolino, Michael E., Nasir, Khurram, Neumar, Robert W., Nichol, Graham,
Palaniappan, Latha, Pandey, Dilip K., Reeves, Mathew J., Rodriguez, Carlos J.,
Rosamond, Wayne, Sorlie, Paul D., Stein, Joel, Towfighi, Amytis, Turan, Tanya
N., Virani, Salim S., Woo, Daniel, Yeh, Robert W., & Turner, Melanie B.
(2016). Heart disease and stroke statistics-2016 update a report from the
American Heart Association. In Circulation (Vol. 133).
https://doi.org/10.1161/CIR.0000000000000350
Savarese, Gianluigi, & Lund, Lars H. (2017). Global public health burden of heart failure. Cardiac
Failure Review, 3(1), 7.
Schmidt, Rodrigo, Rodrigues, Clarissa Garcia, Schmidt, Kelen Heinrich, &
Irigoyen, Maria Claudia Costa. (2020). Safety and
efficacy of baroreflex activation therapy for heart failure with reduced
ejection fraction: a rapid systematic review. ESC Heart Failure, 7(1),
3�14.
Siswanto, Bambang Budi. (2013). Heart
Failure in Indonesia. Journal of Cardiac Failure, 19(10), S108.
https://doi.org/10.1016/j.cardfail.2013.08.027
Wallbach, Manuel, Halbach, Marcel, Reuter, Hannes, Passauer,
Jens, L�ders, Stephan, B�hning, Enrico, Zenker, Dieter, M�ller, Gerhard A.,
Wachter, Rolf, & Koziolek, Michael J. (2016).
Baroreflex activation therapy in patients with prior renal denervation. Journal
of Hypertension, 34(8), 1630�1638.
Zile, Michael R., Abraham, William T., Weaver, Fred A., Butter, Christian,
Ducharme, Anique, Halbach, Marcel, Klug, Didier, Lovett, Eric G.,
M�ller-Ehmsen, Jochen, Schafer, Jill E., Senni, Michele, Swarup, Vijay,
Wachter, Rolf, & Little, William C. (2015).
Baroreflex activation therapy for the treatment of heart failure with a reduced
ejection fraction: Safety and efficacy in patients with and without cardiac
resynchronization therapy. European Journal of Heart
Failure, 17(10), 1066�1074. https://doi.org/10.1002/ejhf.299
Zile, Michael R., Abraham, William T., Weaver, Fred A., Butter, Christian,
Ducharme, Anique, Halbach, Marcel, Klug, Didier, Lovett, Eric G., M�ller‐Ehmsen, Jochen,
& Schafer, Jill E. (2015). Baroreflex
activation therapy for the treatment of heart failure with a reduced ejection
fraction: safety and efficacy in patients with and without cardiac
resynchronization therapy. European Journal of Heart Failure, 17(10),
1066�1074.