Evaluating the efficacy, safety, and predictors of failure following cardiac resynchronization therapy in a developing country: an ambispective, multi-center study

Introduction

Background

Heart failure arises from structural abnormalities that exhibit a significant morbidity and mortality rate. Over the years, there have been novel approaches for managing heart failure that effectively decrease mortality rates (1). Nevertheless, heart failure patients who have experienced substantial loss of synergy may exhibit a poor response to appropriate pharmacological intervention (2). Cardiac resynchronization therapies (CRT) have demonstrated outstanding efficacy in the treatment of heart failure, as evidenced by numerous studies (3-5). CRT effectively lowers rates of re-hospitalization and mortality while also enhancing the overall quality of life for patients. The implantation of CRT is recommended in appropriate patients, as stated by the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Failure Society of America (HFSA) (6) and European Society of Cardiology (ESC) (7) heart failure guidelines. The treatment objectives for this patient cohort center on reducing overall mortality, reducing readmission rates, improving clinical symptoms, and enhancing the quality of life (8).

Rationale and knowledge gap

CRT has demonstrated efficacy in the treatment of heart failure, as evidenced by various research studies such as COMPANION, CARE-HF, and MADIT-CRT (9-11). Nevertheless, there was a report that stated 30–50% of CRT patients did not respond to the treatment (12). Numerous studies have shown factors that are linked to a lack of response to CRT (13-15): baseline factors, including the patient’s age, sex, presence of underlying heart failure; any other medical conditions; New York Heart Association (NYHA) classification; prior use of inotropic therapy (dobutamine); and the use of nitrates. Laboratory results, such as hemoglobin levels and estimated glomerular filtration rate, also hold effects on outcomes. Recently, studies also show other characteristics that predict worse outcomes, including right bundle branch block morphology (16), or ischemic etiology (5), and the presence of a cardiac scar (17). On the other hand, atrial fibrillation on electrocardiogram (ECG) may potentially indicate atrioventricular (AV) node dissection and provide information on the duration of the QRS interval (QRS) complex. In developing countries, the implementation of CRT still faces several challenges, including limited financial and healthcare sources. To guarantee the successful implementation of CRT in these countries, strategic programs should prioritize the patient selection process, the awareness enhancement of its efficacy, and the availability of essential instruments. Furthermore, the performance of CRT can be supported through international partnerships and the utilization of local healthcare systems. In Vietnam, only two studies have been conducted on CRT populations with limited size, and no conclusions have been made on predictors of failure (18,19).

Objective

In Vietnam, our study is the third investigation to acquire and examine clinical outcomes in heart failure patients who undergo CRT monitoring and is the pioneering study in Vietnam with the objective to evaluate factors that can predict failure following CRT implantation. We present this article in accordance with the STROCSS reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-408/rc).

Methods

Study setting & eligibility criteria

This is a multicenter, ambispective study that enrolled all CRT implantation patients at five hospitals in Ho Chi Minh City from April 2016 to April 2020: University Medical Center Ho Chi Minh City, Heart Institute of Ho Chi Minh City, Tam Duc Heart Hospital, Thong Nhat Hospital, and Vinmec Central Park Hospital. The retrospective process was only conducted in the Heart Institute of Ho Chi Minh City. The rest of the study was prospectively performed in all five hospitals. The decision to recruit patients in both ways was made due to concerns of slow recruitment. Patients eligible for CRT implantation were those with symptomatic heart failure (NYHA class II–IV), left ventricular ejection fraction (LVEF) ≤35%, and QRS duration ≥130 ms, as per ESC guidelines (20). Exclusion criteria included patients under 18 years of age, those unwilling to participate, and individuals with a life expectancy less than 1 year due to non-cardiac conditions. This designation was completely independent of the researcher. Firstly, cardiologists specializing in cardiovascular diseases (CVDs) would determine if the patient met the criteria for CRT implantation and then consult with arrhythmia specialists to reach a consensus. Afterwards, the highest-ranking medical authority at the hospital would make the final decision on whether or not to perform CRT implantation, once there was consensus from the patient and their family. After the implantation, the patient would continue to be monitored and treated with internal medicine, following the recommended treatment for heart failure with either the maximum or optimal dosage that the patient can tolerate. The non-pharmacological treatment regimens remained unchanged prior to device implantation.

All prospective participants would be monitored up to 1 year after discharge. This evaluation included the assessment of early (defined as complications arose within the first month after implantation) and late complications, all-cause mortality, readmission due to heart failure or other causes, as well as the evaluation of clinical and subclinical parameters such as NYHA functional class, improvement in quality of life (based on changes in the EQ-5D-5L scoring system), changes in ejection fraction, changes in left ventricular size, degree of valve regurgitation, and changes in cardiac rhythm disturbances. Patients were considered to be CRT responsive when there were improvements in clinical examination, less re-hospitalization due to cardiac causes, and no death due to cardiac reasons. There was not a consensus definition of CRT responsive. Therefore, our criteria were meant to align with other studies’ definitions (9-11). Primary outcomes included rehospitalization and mortality rate 1 year after discharge. Secondary outcomes included early and late complications related to the procedure. Non-responsive post implantation was defined as follows: CRT patients who have undergone multiple follow-ups and device adjustments without any improvement in heart failure clinical presentation, resulting in re-hospitalization and mortality due to exacerbated heart failure. Major complications related to CRT implantations included access site bleeding and hematoma, lead dislodgement, infection, pneumothorax, coronary sinus perforation/dissection, cardiac tamponade, or myocardial injury among others (21). A patient was considered “stable” if all the following criteria were met: symptom improvements; follow-up ECG, echocardiography, and device check showed specific improvements (Figure 1). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This research was approved by the Ethics Review Board of the University of Medicine and Pharmacy at Ho Chi Minh City (No. 507/ĐHYD-HĐĐĐ). All participating hospitals/institutions were informed and agreed with this study. Every patient involved in the study signed a consent form to participate.

Figure 1 Study flow. CRT, cardiac resynchronization therapy; HF, heart failure; LVEF, left ventricular ejection fraction; OMT, optimal medical treatment; NYHA, New York Heart Association; EF, ejection fraction; QRS, QRS interval; ECG, electrocardiogram; dFT, defibrillation threshold; SPWMD, septal posterior wall motion delay.

Statistical analysis

Sample size was calculated according to event rate determined on a single population formula:

n=p(1−p)d2×1.962[1]

With (p=0.06; d=0.05), we calculated the size would be: n=87.

p: mortality rate within 1 year of CRT implantation; the value of p was obtained from the COMPANION study. Mortality rate within 1 year of cardiac resynchronization therapy defibrillator (CRT-D) and cardiac resynchronization therapy pacemaker (CRT-P) implantation was 5% and 8%, respectively (9).

d=0.05 means accepted relative error was 5% with 95% confidence interval.

The standard distribution is expressed as an average ± the standard deviation and is compared using a Student’s t-test to evaluate the difference of two variables or an analysis of variance (ANOVA) test when the difference of many variables is needed. If the non-standard distribution is expressed as median, or put aside special circumstances, then retest by means of Skewness and Kurtosis before using Student’s t-test. We also used McNemar’s paired sample T-test to find the differences between the results before and after the treatment. For the purpose of this study, since we needed to do assessment forms at various times (after the procedure, after 1 month, after 3 months, after 6 months, and after 12 months), the regression method used was linear regression with multiple measurements (general linear regression with repeated measures). This method allows the integration of different measurements into one analysis. The other characteristic was that the equation participation variables were implemented as random variables, allowing for unlimited results by the analysis sample. Analyzes were performed one by one for each resulting variable. There were two groups of resulting variables: for the binary (yes/no) group of variables, we use the logistic regression equation; for the quantitative variable, we used the regular linear regression equation to rule out confounding factors.

Data management

Due to the relatively small number of patients assigned to CRT implants, traditional linear regression using frequentist methods may not be appropriate, as some variables could fail to meet the necessary assumptions. To address this, we employed a more robust regression analysis using a Bayesian approach with the Markov chain Monte Carlo (MCMC) technique. This method allows for the incorporation of prior information and accounts for parameter uncertainty, making it well-suited for smaller sample sizes. By leveraging Bayesian regression, we can generate more reliable estimates and credible intervals, ensuring a more accurate understanding of the relationships between the variables in this context. The MCMC regression and engineering equations were programmed in the WinBUGS program, with the first 5,000 loops to set the first parameter (burn-out phase). The calculation result of 20,000 next loop was used to estimate the value of the equation parameters. To ensure the independence of calculated values, we only store the results after each of the ten calculation loops. Statistically significant threshold α=0.05. The statistical test used was test Z of the normal distribution. Within 4 years, we enrolled total of 88 CRT implantation participants, 11 of them were non-responsive.

Results

Patients characteristics and laboratory results

Over the course of a four-year study, spanning from April 2016 to April 2020, we collected data from five hospitals and documented 88 cases of successful CRT implantation. Characteristics of the study population is shown in Table 1.

The study included individuals ranging in age from 21 to 91 years. The age group with the highest rate of CRT implantation was 60 to 69 years, with a rate of 37.5%. The male-to-female ratio of patients receiving a CRT implant was 2:1. There was no statistically significant difference in the mean age at which CRT implantation occurs between males and females (P=0.4). The majority of patients were NYHA III or IV at admission. There was only one patient with NYHA II heart failure to get CRT implantation due to severe left ventricular end-diastolic dilatation (100 mm), LVEF of 10% and ventricular arrhythmias.

There were 83 patients (94.3%) who had undergone coronary angiography. We noted that 50% of CRT patients had secondary dilated cardiomyopathy heart failure, which was caused by hypertension, diabetes, alcohol abuse, arrhythmias, and after valvular surgery. There were 42% of CRT patients with primary dilated myocardiopathy heart failure. Only 8% had heart failure due to ischemic heart disease. Three patients were performed percutaneous coronary intervention, while the other two had coronary artery bypass grafting (CABG) and the rest were medically treated due to small coronary artery size and extensive lesions. These seven patients were closely monitored after discharge with titrated medications when suitable. After 6 months, they did not improve clinically. Therefore, we decided to perform CRT on them.

The heart failure medications were used during inhospital phase included beta blockers (77.3%), angiotensin-converting enzyme inhibitor (ACEI) (59.1%), angiotensin receptor neprilysin inhibitor (ARNI) (2.3%), angiotensin ii receptor blockers (ARB) (38.6%), magnetic resonance angiography (MRA) (72.7%), sodium-glucose cotransporter 2 inhibitor (SGLT2i) (13.4%), digoxin (76.1%) and furosemide (96.6%). Digoxin usage rate was high, basically due to the traditional way of heart failure description in the country.

CRT technical parameters

Among 88 participants, there was one case we were unable to implant the left ventricular electrical wire into the coronary sinus. Therefore, we had to perform thoracic surgery to get to the left ventricle and implant the wire into the epicardial layer. Specific parameters of all the CRT procedures are shown in Table 2. Figure 2 also displays a representative case of CRT implantation in the study.

Figure 2 Final fluoroscopy image of one CRT implantation case in the study. CRT, cardiac resynchronization therapy; AP, anterior-to-posterior.

Effective profile of CRT implantation

NYHA classification, heart rate and LVEF changes after CRT implantation

We obtained NYHA classification information in 82/88 patients (93.2%) at 1-year follow up (6 patients died during the first year). NYHA classification improved significantly (one NYHA II, one NYHA III and two NYHA IV cases stayed the same. One NYHA III case progressed to NYHA IV; 64 cases shifted from NYHA III to NYHA II/I; 13 cases migrated from NYHA IV to NYHA III/II; by conducting a McNemar test P<0.001) (Table 3).

Heart rate and LVEF improved significantly beginning 3 months after implantation and continuing thereafter (Table 4).

Quality-of-life score changes after CRT implantation

Quality of life (Table 5) increased significantly after CRT implantation according to EQ-5D-5L score changes (P=0.001).

All-cause mortality and rehospitalization rate

We were able to follow up with all 88 of the enrolled participants. We noted 11 deaths (12.5%), six of them happened within 1 year (6.8%) after implantation, five others happened after 1 year (5.7%).

As shown in Figure 3, 100% patients were hospitalized at least one time due to heart failure before CRT implantation. There was significant decreasing in rehospitalization rate 1 year after implantation compared to their own rehospitalization rate before implantation (P=0.001).

Figure 3 Heart failure rehospitalization rate before and after CRT implantation. CRT, cardiac resynchronization therapy.

Safe profile and predictors of non-response to CRT

Safe profile of CRT implantation

In terms of early complications, there was no report of cardiac arrest, heart perforation, or pericardial effusion. There were eight early complication instances (9.1%) following CRT implantation, including one pleural effusion, two infections, two hematomas, two lead dislodgement, and one ventricular arrythmia occurrence. All early problem cases were successfully handled and discharged. Late complications after CRT implantations were mostly due to inappropriate shocks (Table 6). In addition, there were 3/88 cases (3.4%) with electrical storms due to worsening heart failure. No electrical storm appeared due to CRT-D device.

Mortality-related factors (non-responsive factors)

We performed multivariate analysis using a linear regression model using the frequency or regression method with the Bayesian approach (Table 7).

Five factors were associated with CRT non-responsiveness that led to fatalities: history of dobutamine usage, QRS length before implantation, severe ventricular arrhythmias before implantation, atrial fibrillation after implantation, and severe ventricular arrhythmias after implantation. Pre-implantation arrhythmias burden was recorded based on routine ECG and 24-hour Holter ECG, which consisted of non-sustained ventricular tachycardia (68.2%), sustained ventricular tachycardia (12.5%), torsade de pointes (1.1%) and ventricular fibrillation (2.3%).

Discussion

During the research period from April 2016 to April 2020, at five hospitals (University Medical Center Ho Chi Minh City, Heart Institute of Ho Chi Minh City, Tam Duc Heart Hospital, Thong Nhat Hospital, and Vinmec Central Park Hospital), we recruited 88 successful cases of implanting the device that met the study conditions. After the implantation, patients continued to be monitored and treated as standard regimens for heart failure treatment as recommended.

Our study revealed that 87.5% of patients exhibited a positive response to a CRT. A 2022 study by experts from the Republic of Moldova showed that CRT yields excellent outcomes in heart failure patients, particularly noting a decreased death rate in individuals with left bundle branch block and reduced ejection fraction (4). In the same year, the authors of the LOT-ICD trial revealed cost-effective outcomes concerning CRT in patients indicated for CRT-D. They also reported less fluoroscopy duration and radiation exposure (22). Currently, there is no universal definition for responsive CRT implantation (23). The most common used definition for non-responsive is adapted for CRT patients who have undergone multiple follow-ups and device adjustments without any improvement in heart failure clinical presentation, resulting in re-hospitalization and mortality due to exacerbated heart failure. In our study, a total of 6 patients died within the first year, while five patients died within the second year after discharge. To compare with similar studies, Higgin’s study involving 245 patients reported a response rate of 74% (24). Similarly, Young et al.’s study (25) with 187 patients reported a machine response rate of 70%. Other studies conducted by Molhoek et al. and Yeim et al. also yielded comparable results (26,27). The meta-analysis conducted by Varma et al. included a total of 1,327 patients, with a response rate of 83% to CRT (28). Our study observed greater response rates, potentially due to a variation in patient selection. This could be attributed to the fact that the cost of equipment is exorbitant, leading clinicians to prioritize transplant patients, particularly those with type IA designations. Besides, our study found that the percentage of individuals suffering from heart failure due to ischemic heart disease was quite small, approximately 8%. Studies proved that, although ischemic cardiomyopathy resolved its cause, the prognosis of improved treatment of heart failure, particularly the response to CRT, was also generally poorer for patients with dilated cardiomyopathy (11,13). Varma et al. found that the presence or absence of a CRT response in a group of patients with heart failure due to dilated cardiomyopathy was better than that of patients with heart failure due to ischemic heart disease (P=0.003) (28). This is primarily due to the presence of old scar tissue in the affected region of the heart, which renders it unresponsive even if the electrode is placed in an area previously affected by a heart attack. Consequently, achieving resynchronization through the use of the machine is highly unlikely in such cases (29,30). The co-morbidity of heart failure also played a significant role in CRT patients’ outcomes. Specifically, diabetes could affect clinical outcomes (31,32), via negative effects exerted at level of device functionality (33), and at epigenetic level (34). Even the hyperglycemic condition alone can affect CRT response at 1 year after adjusting for other confounders such as age, diabetes, and hypertension (35).

Among the total of 88 patients enrolled in our study, there were 86 patients (97.7%) who implanted a CRT with a sinus rhythm. There were two patients who had paroxysmal atrial fibrillation, which accounted for 2.3%. According to the current heart failure guidelines (6,7), class IIa is recommended for CRT implantation in patients with paroxysmal or refractory atrial fibrillation. In a study by Gasparini et al., after a 4-year follow-up, patients with CRT-implanted atrial fibrillation showed minimal improvement in their ejection fraction, left ventricular diameter, or functional symptoms (36). However, there was something really interesting about this study: if they had an AV nodal conduction cut, then this group of patients would still have a good response to the CRT in nearly a group of patients with a sinus rhythm (36). Additionally, if we programmed the CRT such that the left ventricular tachycardia was greater than 98%, patients with atrial fibrillation still responded well to the CRT (37). Thus, for patients with atrial fibrillation, we consider selecting a programmable left ventricular response when atrial fibrillation is present. This new programming method has been around for 3 years, thanks to the adaptive CRT feature, which has increased the CRT response rate by 46% (38).

The response to a CRT implantation is contingent upon several variables, including the patient’s pre-implanted medical condition, the type of CRT chosen, the position of the left ventricular electrode, and the occurrence of arrhythmias after implantation. Recently, Sardu et al. (39) reported the role of endothelial dysfunction in the response of heart failure patients with CRT implantation. They investigated a new biomarker, serum miR-130a-5p, in predicting CRT response, and the result was promising. However, the most critical determinant in enhancing the CRT’s response rate is the proficiency of the machine programming team in delivering optimal results. In the event that the CRT was programmed autonomously and the patient exhibited signs of non-compliance, a reevaluation would be necessary to determine the cause of the failure. The proportion of patients who initially do not respond to CRT is approximately one-third, according to a study (40). Forty-eight patients (54.5%) in our study did not respond initially; therefore, the CRT had to be reprogrammed. This implies that one patient had to be reprogrammed for every two patients. The reason that the CRT does not respond is a challenging one to explain. However, the response of the CRT may be limited by the following: individuals diagnosed with coronary artery disease exhibit a reduced level of responsiveness in comparison to those without the condition (41). A positive correlation exists between the width of the QRS and response quality. Additionally, the absence of left bundle branch block or atrial fibrillation prior to or following machine implantation can impact response rates. Three significant causes of inadequate response to initial CRT were identified in our study: patients who had received a dobutamine dose prior to this one (P=0.002), high levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) (P=0.004), and low LVEF (P=0.007). When the patient exhibits no clinical improvement, no change in NYHA ratings, and no improvement in left ventricular function, it is advisable to modify the CRT (42). In order to improve response rate or achieve a better result than the initial one, the following adjustments should be made to the ECG or echocardiography equipment: QRS width should not decrease, ECG should not exhibit R/S ≥1 in V1 or R/S ≤1 in D1, echocardiography should reveal an ejection fraction (EF) improvement of less than 20% over the initial EF, defibrillation threshold (dFT) should shorten to 45% of the EA wave, and septal-to-posterior wall motion delay should exceed 150 Ms. Another aspect that could affect CRT response and lead to better clinical outcomes is angiotensin receptor/neprilysin inhibitor (ARNI) usage (43). Main effects are due to anti-remodeling effects via the modulation of epigenetic pathways (43) and the reduction of inflammatory burden, which is tightly linked to CVD and worse clinical outcomes (44). Two patients received ARNI in our study. The limited quantity is attributable to the lack of popularity of ARNI in Vietnam during this investigation.

In our study, the mean ejection fraction was 24%, with a maximum of 35% and a minimum of 10%. This outcome aligns with global studies, which report an average EF within the range of 23–29%, including the PROSPECT study (13) and the research conducted by Varma et al. (28). Post-CRT implantation, the mean ejection fraction improved, with an average EF of 27.7% at 3 months, 32.1% at 6 months, and 36.6% at 1 year, demonstrating statistical significance (P<0.001). This indicated that the ejection fraction significantly altered following CRT implantation and progressively improved over time, contingent upon the patient’s favorable response to the device. The ejection fraction results in our study seem to exceed those reported in some of the aforementioned studies. This may be attributed to the fact that, in our investigation, patients assigned to implanted CRT exhibited a decreased incidence of ischemic cardiomyopathy compared to the other studies. Sherazi et al.’s research indicates that CRT enhances left ventricular function (45). The mean end-diastolic left ventricular diameter in our study was 69.5 mm, while the mean end-systolic left ventricular diameter was 58.9 mm. After 1 year, the mean end-diastolic left ventricular diameter is 67.81 mm, with a statistically significant difference (P=0.009). The mean end-systolic left ventricular diameter is 51.48 mm, also demonstrating a statistically significant difference (P<0.001). The CRT has demonstrated the ability to reverse left ventricular anatomy, enhancing the size of the left heart chamber. Structural alterations in the left ventricle become apparent by the third month and progressively intensify from the sixth month, with further prolongation observed subsequently, as demonstrated by the CARE-HF study.

Our research indicates a significant correlation between the lack of response to CRT and various factors that contribute to the persistence of heart failure. These factors include the extent of the QRS complex before implantation of the device, the use of dobutamine as a precursor, the presence of a severe ventricular rhythm disturbance prior to implantation, the occurrence of paroxysmal atrial fibrillation after implantation, and the presence of severe ventricular arrhythmias after implantation. It is well understood that a patient who succumbs to heart failure is influenced by numerous factors. The utilization of dobutamine is associated with adverse outcomes following CRT installation. This outcome parallels the study conducted by Varma et al. (28). The study had 1,327 patients, of whom 107 received dobutamine (8.1%), and 30 did not react to cardiac resynchronization therapy (CRT) (38.9%, P=0.029). Hansky et al. (46) have proposed that CRT implantation in unstable heart failure patients may result in poorer outcomes. The QRS length prior to implantation is globally recognized as an independent predictor of mortality in individuals with significantly reduced ejection fraction. QRS duration exceeding 150 ms typically shows a favorable response to CRT compared to the cohort with QRS duration less than 150 ms in the COMPANION, CARE-HF, and MADIT-CRT investigations (9-11). Consequently, an enhancement in QRS duration serves as a reliable predictor and correlates with increased survival rates in heart failure patients exhibiting lower ejection fraction and prolonged QRS duration. Conversely, ventricular arrhythmia has been demonstrated to correspond with poorer outcomes in heart failure (47-49). A significant incidence of ventricular arrhythmia exists in heart failure patients with decreased ejection fraction. In most instances, ventricular arrhythmia is a consequence of heart failure resulting from myocardial damage, however it can potentially precipitate heart failure. Patients with advanced heart failure commonly utilize certain drugs that may increase the risk of arrhythmias: digoxin and dobutamine (50). This ventricular arrhythmia can result in abrupt cardiac death in heart failure and also exacerbates adverse outcomes. In the meta-analysis conducted by Varma et al. involving 1,327 patients, the prevalence of atrial fibrillation prior to and following CRT implantation was 38.4%. A statistically significant difference in response to CRT was observed between the two groups, with P=0.002 (28). Heart failure is a distinct risk factor for atrial fibrillation, exhibiting an odds ratio of 3.2. New-onset atrial fibrillation exacerbates heart failure, as evidenced by peak oxygen consumption exceeding that of anaerobic metabolism (51). Atrial fibrillation elevates mortality in heart failure patients by 2.7 in males and 3.1 in females. Atrial fibrillation in CRT patients impedes left ventricular function, resulting in a lack of response to CRT. These data lead to the conclusion that atrial fibrillation is a risk factor for increased mortality in patients undergoing CRT implantation. Should we be able to anticipate atrial fibrillation post-implantation, it is advisable to contemplate AV nodal ablation prior to CRT implantation. In the presence of atrial fibrillation following CRT installation, prompt consideration of AV nodal ablation is advised. We should select newer generation CRT devices that incorporate atrial fibrillation reduction programming to identify patients at a higher risk of developing atrial fibrillation following CRT implantation.

Furthermore, the patient’s reaction to CRT is influenced by various parameters, including the specific type of CRT machine and the features of the left ventricular electrodes. These factors contribute to the improvement of the patient’s readmission and mortality rates (28). The favorable outcome of this study advocates for the integration of CRT into clinical practice in Vietnam. The scarcity of accessible data on CRT in a developing nation has impeded clinicians from translating knowledge into practice. The increased cost was also a factor in the feasibility of changing clinical guidelines for CRT in heart failure patients. We believe that the favorable results and precise linkages between particular population features and outcomes will significantly influence clinical guidance. Consequently, we would witness enhancements in CRT accessibility and routine practice.

The study was subject to several limitations. To begin with, the study’s ambispective nature, not having a control group, and the limited sample size restricted its ability to make significant recommendations. The limited sample size also did not reflect the underused CRT situation in female patients, despite the well-established benefit in this sub-group (52). While the method remains accurate in terms of study approaches, we believe it is appropriate to undertake this study to highlight which patient groups should be given even more cautions, as CRT have been given clear indication in heart failure recommendations. Additionally, there is a possibility that some of the collected information may be not sufficiently accurate and may be with missing information, particularly with the medication dosage. The timing of patient follow-up is inconsistent, with some patients having received CRT for several years. Besides, while some patients had just undergone CRT implantation, others exhibited significant variability in their data collection. Finally, due to missing data, we could not obtain the medical treatment post-implantation. Future research is needed, especially in an older population and for a longer follow-up period.

Conclusions

This study retained its status as the most extensively conducted study in Vietnam, a country with a low-income level. When utilized correctly, the insertion of a CRT device holds the capacity to substantially reduce symptoms, mortality rates, and the probability of readmission in patients afflicted with heart failure. Several indicators can be indicative of a lack of response to cardiac resynchronization therapies: previous administration of dobutamine, increased QRS complex width, occurrence of ventricular arrhythmias before or after CRT placement, and the development of atrial fibrillation following CRT placement. This information enables us to gain a deeper comprehension of the distinctive attributes of the restricted patient cohort, facilitating the implementation of more pertinent interventions in subsequent instances.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROCSS reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-408/rc

Data Sharing Statement: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-408/dss

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-408/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-408/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This research was approved by the Ethics Review Board of University of Medicine and Pharmacy at Ho Chi Minh City (No. 507/ĐHYD-HĐĐĐ). All participating hospitals/institutions were informed and agreed with this study. Every patient involved in the study signed a consent form to participate.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sapna F, Raveena F, Chandio M, et al. Advancements in Heart Failure Management: A Comprehensive Narrative Review of Emerging Therapies. Cureus 2023;15:e46486. [Crossref] [PubMed]
2. Prinzen FW, Auricchio A, Mullens W, et al. Electrical management of heart failure: from pathophysiology to treatment. Eur Heart J 2022;43:1917-27. [Crossref] [PubMed]
3. Linde C. Cardiac resynchronization in heart failure: Recent advances and their practical implications. Kardiol Pol 2023;81:7-13. [Crossref] [PubMed]
4. Darciuc R, Boiciuc I, Ivanov D, et al. Cardiac resynchronization therapy in the Republic of Moldova: The beginning of the journey. Heart Rhythm O2 2022;3:728-30. [Crossref] [PubMed]
5. Yokoshiki H, Shimizu A, Mitsuhashi T, et al. Cardiac resynchronization therapy with a defibrillator in non-ischemic and ischemic patients for primary and secondary prevention of sudden cardiac death: Analysis of the Japan cardiac device treatment registry database. J Arrhythm 2023;39:757-65. [Crossref] [PubMed]
6. Heidenreich PA, Bozkurt B, Aguilar D, 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. Circulation 2022;145:e895-e1032. [Crossref] [PubMed]
7. McDonagh TA, Metra M, Adamo M, et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2023;44:3627-39. [Crossref] [PubMed]
8. Okunade O. Choices in Heart Failure Treatment Goals: The Role of Patient-Reported Health Status. JACC Heart Fail 2019;7:942-4. [Crossref] [PubMed]
9. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140-50. [Crossref] [PubMed]
10. Cleland JG, Daubert JC, Erdmann E, et al. Longer-term effects of cardiac resynchronization therapy on mortality in heart failure [the CArdiac REsynchronization-Heart Failure (CARE-HF) trial extension phase]. Eur Heart J 2006;27:1928-32. [Crossref] [PubMed]
11. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329-38. [Crossref] [PubMed]
12. Sieniewicz BJ, Gould J, Porter B, et al. Understanding non-response to cardiac resynchronisation therapy: common problems and potential solutions. Heart Fail Rev 2019;24:41-54. [Crossref] [PubMed]
13. Chung ES, Leon AR, Tavazzi L, et al. Results of the Predictors of Response to CRT (PROSPECT) trial. Circulation 2008;117:2608-16. [Crossref] [PubMed]
14. Kawata H, Bao H, Curtis JP, et al. Cardiac Resynchronization Defibrillator Therapy for Nonspecific Intraventricular Conduction Delay Versus Right Bundle Branch Block. J Am Coll Cardiol 2019;73:3082-99. [Crossref] [PubMed]
15. Allison JD Jr, Biton Y, Mela T. Determinants of Response to Cardiac Resynchronization Therapy. J Innov Card Rhythm Manag 2022;13:4994-5003. [Crossref] [PubMed]
16. Friedman DJ, Al-Khatib SM, Dalgaard F, et al. Cardiac Resynchronization Therapy Improves Outcomes in Patients With Intraventricular Conduction Delay But Not Right Bundle Branch Block: A Patient-Level Meta-Analysis of Randomized Controlled Trials. Circulation 2023;147:812-23. [Crossref] [PubMed]
17. Maffessanti F, Jadczyk T, Wilczek J, et al. Electromechanical factors associated with favourable outcome in cardiac resynchronization therapy. Europace 2023;25:546-53. [Crossref] [PubMed]
18. Hung PN. Treatment of severe heart failure patients with cardiac resynchronization device. Doctor of philosophy thesis, Hanoi Medical University 2012:56-99.
19. Minh HV, Dien NV, Tien HA. Early results of cardiac resynchronization therapy in heart failure patients at Hue University of Medicine and Pharmacy Hospital Journal of Vietnamese Cardiology 2011:367-72.
20. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129-200. [Crossref] [PubMed]
21. Ahmed I, Kayani WT. Cardiac Resynchronization Therapy. In: StatPearls. Treasure Island (FL): StatPearls Publishing; July 30, 2023.
22. Ponnusamy SS, Ramalingam V, Ganesan V, et al. Left bundle branch pacing-optimized implantable cardioverter-defibrillator (LOT-ICD) for cardiac resynchronization therapy: A pilot study. Heart Rhythm O2 2022;3:723-7. [Crossref] [PubMed]
23. Gerra L, Bonini N, Mei DA, et al. Cardiac resynchronization therapy (CRT) nonresponders in the contemporary era: A state-of-the-art review. Heart Rhythm 2025;22:159-69. [Crossref] [PubMed]
24. Higgins SL, Hummel JD, Niazi IK, et al. Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol 2003;42:1454-9. [Crossref] [PubMed]
25. Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 2003;289:2685-94. [Crossref] [PubMed]
26. Molhoek SG, Bax JJ, Bleeker GB, et al. Long-term follow-up of cardiac resynchronization therapy in patients with end-stage heart failure. J Cardiovasc Electrophysiol 2005;16:701-7. [Crossref] [PubMed]
27. Yeim S, Bordachar P, Reuter S, et al. Predictors of a positive response to biventricular pacing in patients with severe heart failure and ventricular conduction delay. Pacing Clin Electrophysiol 2007;30:970-5. [Crossref] [PubMed]
28. Varma N, Boehmer J, Bhargava K, et al. Evaluation, Management, and Outcomes of Patients Poorly Responsive to Cardiac Resynchronization Device Therapy. J Am Coll Cardiol 2019;74:2588-603. [Crossref] [PubMed]
29. Linde C, Abraham WT, Gold MR, et al. Cardiac resynchronization therapy in asymptomatic or mildly symptomatic heart failure patients in relation to etiology: results from the REVERSE (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction) study. J Am Coll Cardiol 2010;56:1826-31. [Crossref] [PubMed]
30. St John Sutton M, Ghio S, Plappert T, et al. Cardiac resynchronization induces major structural and functional reverse remodeling in patients with New York Heart Association class I/II heart failure. Circulation 2009;120:1858-65. [Crossref] [PubMed]
31. Sardu C, Paolisso P, Ducceschi V, et al. Cardiac resynchronization therapy and its effects in patients with type 2 DIAbetes mellitus OPTimized in automatic vs. echo guided approach. Data from the DIA-OPTA investigators. Cardiovasc Diabetol 2020;19:202. [Crossref] [PubMed]
32. Sardu C, Barbieri M, Santamaria M, et al. Multipolar pacing by cardiac resynchronization therapy with a defibrillators treatment in type 2 diabetes mellitus failing heart patients: impact on responders rate, and clinical outcomes. Cardiovasc Diabetol 2017;16:75. [Crossref] [PubMed]
33. Sardu C, Marfella R, Santamaria M, et al. Stretch, Injury and Inflammation Markers Evaluation to Predict Clinical Outcomes After Implantable Cardioverter Defibrillator Therapy in Heart Failure Patients With Metabolic Syndrome. Front Physiol 2018;9:758. [Crossref] [PubMed]
34. Sardu C, Barbieri M, Rizzo MR, et al. Cardiac Resynchronization Therapy Outcomes in Type 2 Diabetic Patients: Role of MicroRNA Changes. J Diabetes Res 2016;2016:7292564. [Crossref] [PubMed]
35. Gambardella J, Jankauskas SS, D'Ascia SL, et al. Glycation of ryanodine receptor in circulating lymphocytes predicts the response to cardiac resynchronization therapy. J Heart Lung Transplant 2022;41:438-41. [Crossref] [PubMed]
36. Gasparini M, Auricchio A, Regoli F, et al. Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation. J Am Coll Cardiol 2006;48:734-43. [Crossref] [PubMed]
37. Jacobsson J, Reitan C, Carlson J, et al. Atrial fibrillation incidence and impact of biventricular pacing on long-term outcome in patients with heart failure treated with cardiac resynchronization therapy. BMC Cardiovasc Disord 2019;19:195. [Crossref] [PubMed]
38. Birnie D, Hudnall H, Lemke B, et al. Continuous optimization of cardiac resynchronization therapy reduces atrial fibrillation in heart failure patients: Results of the Adaptive Cardiac Resynchronization Therapy Trial. Heart Rhythm 2017;14:1820-5. [Crossref] [PubMed]
39. Sardu C, Santulli G, Savarese G, et al. Endothelial Dysfunction Drives CRTd Outcome at 1-Year Follow-Up: A Novel Role as Biomarker for miR-130a-5p. Int J Mol Sci 2023;24:1510. [Crossref] [PubMed]
40. Tolosana JM, Mont L. Cardiac Resynchronization Therapy: How to Decrease Nonresponders. Card Electrophysiol Clin 2015;7:789-96. [Crossref] [PubMed]
41. Varma N, Lappe J, He J, et al. Sex-Specific Response to Cardiac Resynchronization Therapy: Effect of Left Ventricular Size and QRS Duration in Left Bundle Branch Block. JACC Clin Electrophysiol 2017;3:844-53. [Crossref] [PubMed]
42. van Bommel RJ, Bax JJ, Abraham WT, et al. Characteristics of heart failure patients associated with good and poor response to cardiac resynchronization therapy: a PROSPECT (Predictors of Response to CRT) sub-analysis. Eur Heart J 2009;30:2470-7. [Crossref] [PubMed]
43. Sardu C, Massetti M, Scisciola L, et al. Angiotensin receptor/Neprilysin inhibitor effects in CRTd non-responders: From epigenetic to clinical beside. Pharmacol Res 2022;182:106303. [Crossref] [PubMed]
44. Sardu C, Paolisso G, Marfella R. Inflammatory Related Cardiovascular Diseases: From Molecular Mechanisms to Therapeutic Targets. Curr Pharm Des 2020;26:2565-73. [Crossref] [PubMed]
45. Sherazi S, Shah F, Kutyifa V, et al. Risk of Ventricular Tachyarrhythmic Events in Patients Who Improved Beyond Guidelines for a Defibrillator in MADIT-CRT. JACC Clin Electrophysiol 2019;5:1172-81. [Crossref] [PubMed]
46. Hansky B, Schulte-Eistrup S, Vogt J, et al. Lead selection and implantation technique for biventricular pacing. Eur Heart J Suppl 2004;6:D112-D116. [Crossref]
47. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225-37. [Crossref] [PubMed]
48. Cleland JG, Chattopadhyay S, Khand A, et al. Prevalence and incidence of arrhythmias and sudden death in heart failure. Heart Fail Rev 2002;7:229-42. [Crossref] [PubMed]
49. Liao YC, Hsieh YC, Hung CY, et al. Statin therapy reduces the risk of ventricular arrhythmias, sudden cardiac death, and mortality in heart failure patients: a nationwide population-based cohort study. Int J Cardiol 2013;168:4805-7. [Crossref] [PubMed]
50. Whitman IR, Feldman HI, Deo R. CKD and sudden cardiac death: epidemiology, mechanisms, and therapeutic approaches. J Am Soc Nephrol 2012;23:1929-39. [Crossref] [PubMed]
51. Agostoni P, Emdin M, Corrà U, et al. Permanent atrial fibrillation affects exercise capacity in chronic heart failure patients. Eur Heart J 2008;29:2367-72. [Crossref] [PubMed]
52. Mullens W, Auricchio A, Martens P, et al. Optimized implementation of cardiac resynchronization therapy: a call for action for referral and optimization of care: A joint position statement from the Heart Failure Association (HFA), European Heart Rhythm Association (EHRA), and European Association of Cardiovascular Imaging (EACVI) of the European Society of Cardiology. Eur J Heart Fail 2020;22:2349-69. [Crossref] [PubMed]