Next Article in Journal
Preimplantation Genetic Testing (PGT) and Prenatal Diagnosis of Schaaf-Yang Syndrome: A Report of Three Families and a Research on Genotype–Phenotype Correlations
Next Article in Special Issue
Peri-Procedural Management of Direct-Acting Oral Anticoagulants (DOACs) in Transcatheter Miniaturized Leadless Pacemaker Implantation
Previous Article in Journal
Chronic Low Back Pain: A Narrative Review of Recent International Guidelines for Diagnosis and Conservative Treatment
Previous Article in Special Issue
Conduction System Pacing Today and Tomorrow
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 12
Issue 4
10.3390/jcm12041686
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Systematic Review

Effect of Digitalis on ICD or CRT-D Recipients: A Systematic Review and Meta-Analysis

by
Wen Zhuo
1,†,
Hualong Liu
1,†,
Linghua Fu
1,
Weiguo Fan
1 and
Kui Hong
1,2,3,*
1
Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
2
Jiangxi Key Laboratory of Molecular Medicine, Nanchang 330006, China
3
Department of Genetic Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
J. Clin. Med. 2023, 12(4), 1686; https://doi.org/10.3390/jcm12041686
Submission received: 21 January 2023 / Revised: 14 February 2023 / Accepted: 15 February 2023 / Published: 20 February 2023
(This article belongs to the Special Issue Advances in Cardiac Pacing and Cardiac Resynchronization Therapy)
Browse Figures
Versions Notes

Abstract

:
Background: Digitalis has been widely utilized for heart failure therapy and several studies have demonstrated an association of digitalis and adverse outcome events in patients receiving implantable cardioverter defibrillators (ICDs) or cardiac resynchronization therapy defibrillators (CRT-Ds). Hence, we conducted this meta-analysis to assess the effect of digitalis on ICD or CRT-D recipients. Methods: We systematically retrieved relevant studies using the Cochrane Library, PubMed, and Embase database. A random effect model was used to pool the effect estimates (hazard ratios (HRs) and 95% confidence intervals (CIs)) when the studies were of high heterogeneity, otherwise a fixed effect model was used. Results: Twenty-one articles containing 44,761 ICD or CRT-D recipients were included. Digitalis was associated with an increased rate of appropriate shocks (HR = 1.65, 95% CI: 1.46–1.86, p < 0.001) and a shortened time to first appropriate shock (HR = 1.76, 95% CI: 1.17–2.65, p = 0.007) in ICD or CRT-D recipients. Furthermore, the all-cause mortality increased in ICD recipients with digitalis therapy (HR = 1.70, 95% CI: 1.34–2.16, p < 0.01), but the all-cause mortality was unchanged in CRT-D recipients (HR = 1.55, 95% CI: 0.92–2.60, p = 0.10) or patients who received ICD or CRT-D therapy (HR = 1.09, 95% CI: 0.80–1.48, p = 0.20). The sensitivity analyses confirmed the robustness of the results. Conclusion: ICD recipients with digitalis therapy may tend to have higher mortality rates, but digitalis may not be associated with the mortality rate of CRT-D recipients. Further studies are required to confirm the effects of digitalis on ICD or CRT-D recipients.

1. Introduction

Heart failure (HF) and atrial fibrillation (AF) were predicted to become epidemics of the 21st century. HF is a major and growing public health problem that leads to considerable morbidity and mortality and AF, as well as AF-related complications, results in substantial cardiovascular morbidity and mortality [1]. Digitalis, a kind of cardiac glycosides, was widely used in HF patients for its positive inotrope effect and in AF patients for its negative dromotropic activity effect to slow the rate of ventricular contraction in patients with an atrial flutter or AF [2,3]. A randomized controlled trial named the Digitalis Investigation Group (DIG) trial has discovered a reduction in hospitalization rates and improvements in HF symptoms but no reduction in mortality [4]. Based on the results of the DIG trial, the current guidelines recommended digitalis as a Class IIb indication with a B level of evidence to decrease hospitalizations for HF patients [5,6].
Cardiac implantable electronic devices, such as implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy defibrillators (CRT-Ds), are interventional therapies that can mitigate the risk of sudden cardiac death (SCD) in patients with high-risk ventricular arrhythmia [7,8]. ICD or CRT-D therapy is recommended in HF patients whose left ventricular ejection fractions (LVEF) < 35% in NYHA II or III, for ICDs or CRT-Ds could monitor heart rate and prevent SCD by appropriate shocks when ventricular tachycardia/fibrillation (VT/VF) are detected [9]. Nevertheless, recent studies have found an increased risk of VT/VF and mortality in HF patients treated with digoxin [10,11], which is in contrast to findings from previous studies. Given this incompatible evidence, the effect of digitalis on ICD or CRT-D recipients is still not completely understood. Hence, we conducted this systematic review and meta-analysis to evaluate whether digitalis is associated with an increased rate of appropriate shocks or mortality in patients who receive ICD or CRT-D implantations.

2. Methods

The authors declare that all supporting data are available within the article and its online supplementary files.

2.1. Search Strategy

We systematically searched PubMed, Embase, and Cochrane library for relevant articles up until 1 November 2022 and these articles were selected independently by two authors (W.Z. and H.-L.L.). The MeSH terms and text words were used for retrieving articles in PubMed, while Emtree terms and text words were searched in Embase. A group of keywords were linked to the therapy (“Defibrillators, Implantable” OR “Implantable Defibrillators” OR “Implantable Defibrillator” OR “Cardioverter-Defibrillators, Implantable” OR “Implantable Cardioverter-Defibrillator” OR “Implantable Cardioverter Defibrillators” OR “Defibrillator, Implantable”). Another group of keywords were linked to the medicine (“Digitalis” OR “Foxglove” OR “Digitalis lanata” OR “Grecian Foxglove” OR “Digitalis purpurea” OR “Common Foxglove” OR “digoxin” OR “Lanacordin” OR “Lanicor” OR “Lanoxicaps” OR “Dilanacin” OR “Digoregen” OR “Digoxina Boehringer” OR “Lanoxin” OR “Lenoxin”). The two groups of keywords were combined using the Boolean operator “AND” and the language restriction was not set. We used Endnote X8 to manage the retrieved articles. The title and abstract were read separately by two authors (W.Z. and H.-L.L.). to assess whether the articles were qualified to be accepted into this meta-analysis; when necessary, the full text was browsed. The two authors reached a consensus after discussing the debatable studies. We excluded the articles that did not meet the inclusion criteria by reasons.

2.2. Selection Criteria

Studies met the inclusion criterion if (1) studies reported digitalis or digoxin use in patients receiving ICD or CRT-D therapy; (2) the hazard ratio (HR), odds ratio (OR), or risk ratio (RR), as well as their corresponding 95% confidence intervals (CIs), were applied to assess the endpoint event risk; (3) studies included population-based or hospital-based patients; (4) the endpoint events were appropriate shocks, time to first appropriate shock, or all-cause mortality.
Studies were excluded if (1) the risk estimates of digitalis use were not mentioned; (2) articles were certain publication types, such as reviews, meta-analyses, letters, notes, editorials, or case reports; (3) the factors had not been adjusted; (4) the full text could not be found.

2.3. Data Extraction and Quality Assessment

The data were extracted from the included articles independently by two reviewers (W.Z. and H.-L.L.) after duplications were removed. The following information was extracted from the articles: author’s name, publication year, study design, country, sample size, follow-up duration, age, sex ratio, patients with AF, LVEF, QRS duration, disease, therapy methods, type of medicine, and outcome event. Adjusted HRs or RRs were extracted when unadjusted and adjusted HRs or RRs were reported. The Newcastle–Ottawa Scale (NOS) was used to evaluate the quality of the included studies. Each study was scored independently by two authors (W.Z. and H.-L.L.) based on three factors: selection, comparability, and outcome. A positive response to a question from the framework was given a score of 1 star and the maximum number of stars each article could obtain was 9. We considered a study with an NOS score greater than 6 stars to be of moderate or high quality. If a study received less than 6 stars, its quality was poor. In addition, our meta-analysis was performed according to the preferred reporting items for systematic reviews and meta-Analyses (PRISMA) guidelines [12].

2.4. Outcomes and Subgroups

The first outcome was defined as the rate of appropriate shocks in ICD or CRT-D recipients. The second outcome was the time to first appropriate shock in patients implanted with an ICD or a CRT-D. The third outcome was the all-cause mortality in ICD or CRT-D recipients who were administered digitalis therapy. For the third outcome, we performed two subgroup analyses. The first aimed to test the relevance of the type of device therapy and all-cause mortality and the second one aimed to test the relevance of digitalis species and all-cause mortality.

2.5. Statistical Analysis

We used Review Manager 5.3 (Cochrane Collaboration, Copenhagen, Denmark) to perform our meta-analysis. HRs were used as the common risk estimates and the natural logarithm of HR (log HR) and its standard error (SElog HR) were calculated according to the confidence intervals. The heterogeneity was evaluated using chi-squared and I-squared tests. Heterogeneity was considered to exist when p-value < 0.10 as assessed by the chi-squared test. An I2 > 50% indicated substantial heterogeneity and the random effects model was used to pool the effect estimates. When I2 < 50%, a fixed effects model was used. Funnel plots were also generated to further evaluate the possibility of heterogeneity. Sensitivity analysis was used to test the impact of individual studies.

3. Results

3.1. Study Selection and Study Characteristics

As shown in Figure 1, we initially identified 1194 articles through electronic retrieval strategies, including 137 in PubMed, 1040 in Embase, and 17 in the Cochrane Library. No additional studies were identified through manual searches. After duplicates were removed, 1081 articles were screened based on titles and abstracts and 998 irrelevant studies were discarded. We screened the full text of the remaining 83 studies and 62 articles were excluded due to the following reasons: (a) the full text of the article could not be located (n = 4); (b) the data of the articles were insufficient or duplicated (n = 5); (c) the articles were off topic (n = 42); (d) the articles were reviews or commentaries (n = 11). Finally, 21 studies [10,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32] encompassing 44,761 ICD or CRT-D recipients were included in this systematic review and meta-analysis.
The baseline characteristics of the studies included in our analysis are presented in Table 1. Among the 21 articles, 10 studies reported the appropriate shock rate [10,13,14,18,21,22,24,26,30,32], 2 studies [13,16] reported the time to the first appropriate shock, and 14 articles reported the mortality of ICD or CRT-D recipients [10,13,15,17,23,25,27,28,29,31,32]. Six of the included articles were prospective studies and fifteen were retrospective studies. The quality of all selected studies was assessed using the Newcastle–Ottawa Scale. All studies included in the analysis had a score ≥7 and the average score was 7.80. The details of the quality assessment are presented in Supplemental Table S1. As shown in Table 1, patients who received digitalis therapy tended to have a wider QRS duration, a lower LVEF, and a higher proportion of AF. Four studies mentioned digitalis dosages and the median prescribed daily dosages were in the recommended range (Supplemental Table S2). The inclusion criteria of the included studies are shown in Supplemental Table S3. The meta-analysis was performed according to the PRISMA guidelines (Supplemental Table S4).

3.2. Digitalis and Appropriate Shocks

In the 21 included studies, 10 studies used appropriate shocks as their endpoint events. Figure 2A showed that digitalis significantly increased the rate of appropriate shocks in ICD or CRT-D recipients (HR = 1.65, 95% CI: 1.46–1.86, p < 0.001), with lack of heterogeneity (I2 = 0%, p = 0.63). As shown in Figure 2B, digitalis shortened the time to the first appropriate shock in patients implanted with ICDs or CRT-Ds (HR = 1.76, 95% CI: 1.17–2.65, p = 0.007). Given the lack of heterogeneity (I2 = 10%, p = 0.29), a fixed effects model was used. No significant publication bias was observed in the studies that reported the appropriate shocks as their outcome event (Supplemental Figure S1) and the results were unchanged after removing individual studies (Supplemental Figure S2).

3.3. Digitalis and All-Cause Mortality

All-cause mortality was reported in 14 articles. Due to the existence of high heterogeneity (I2 = 74%, p < 0.01), a random effects model was used for the pooled HR, with the corresponding 95% CI. As the results showed that the rate of appropriate shocks in ICD or CRT-D recipients significantly increased under digitalis therapy, we aimed to explore the relevance of digitalis and all-cause mortality. As shown in Figure 3A, digitalis increased the risk of all-cause mortality in ICD or CRT-D recipients (HR = 1.53, 95% CI: 1.29–1.82, p < 0.001). Next, we performed a subgroup analysis to test the relevance of the type of device therapy and all-cause mortality. Figure 3B showed that digitalis increased the all-cause mortality of patients treated with ICDs (HR = 1.70, 95% CI: 1.34–2.16, p < 0.001); however, digitalis did not affect the mortality of CRT-Ds recipients (HR = 1.55, 95% CI: 0.92–2.60, p = 0.10) or patients treated with ICD or CRT-D therapy (HR = 1.09, 95% CI: 0.80–1.48, p = 0.20). The corresponding funnel plot showed the possible absence of publication bias (Supplemental Figure S3) and the sensitivity analysis (Supplemental Figure S4) demonstrated that the pooled results were not affected by deleting individual studies. To explore the effect of drug species, we performed an additional subgroup by separating the included studies by drug species. The results showed that the mortality both increased in ICD or CRT-D recipients who received digoxin (HR = 1.43, 95% CI: 1.15–1.77, p = 0.002) and digitalis (HR = 1.66, 95% CI: 1.36–2.01, p < 0.001) (Supplemental Figure S5).

4. Discussion

Inconsistent results have been reported concerning the association between digitalis use and mortality in ICD or CRT-D recipients. Previous studies [15] found that the mortality of ICD recipients increased with digitalis therapy, whereas a recent study [31] could not confirm the harmful effects of digitalis in ICD patients. We pooled 21 articles, including 44,761 patients, to explore the reasonable results. Our analysis showed that ICD or CRT-D recipients who received digitalis therapy suffered a higher rate of appropriate shocks; moreover, digitalis shortened the time to first appropriate shocks in patients treated with ICDs or CRT-Ds. In addition, digitalis was associated with an increased risk of mortality in patients who received ICD implantations, whereas all-cause mortality was unchanged in CRT-D recipients. Despite an absence of randomized controlled trials, the included observational cohort studies were of high quality and met the criteria to conduct this meta-analysis. To the best of our knowledge, this is the first meta-analysis to analyze the association between digitalis and adverse outcomes in patients treated with ICDs or CRT-Ds.

4.1. Possible Mechanisms of Digitalis in Appropriate Device Shocks

ICDs or CRT-Ds could effectively prevent SCD in patients with a high risk of fatal arrhythmia by delivering appropriate device shocks. In general, appropriate shocks are indicators of increased ventricular arrhythmias [33]. Previous studies have found that several factors could influence the delivery of appropriate device shocks, for example, age, diuretic, digitalis, and antiarrhythmic drug use [16]. Our findings show that digitalis tends to increase the rate of appropriate shocks and shortens the time to first appropriate shock in ICD or CRT-D recipients, indicating that digitalis could increase the risk of life-threatening arrhythmias in patients implanted with ICDs or CRT-Ds. The possible mechanism of the potential proarrhythmic effects of digitalis in ICD or CRT-D recipients might be explained as follows. Digitalis has positive inotropic effects by inhibiting Na+/K+-ATPase activity in cardiac myocytes, leading to a reduction in cytosolic Na+ effluxion. Afterwards, the Na+/Ca2+ antiporter is inhibited, which causes an increase in intracellular Ca2+ concentration, ultimately resulting in increased contractility [34]. However, increased intracellular Ca2+ concentrations may increase transient inward depolarizing currents, resulting in the generation of delayed afterdepolarizations [35,36], which may aggravate or induce ventricular arrhythmias. The increased rate of appropriate shocks and the shorter time to first appropriate shock are the consequences of more frequent ventricular arrhythmias that were detected by ICDs or CRT-Ds.

4.2. Possible Mechanisms of Digitalis in Mortality

In addition to assessing the rate of appropriate shocks, we analyzed all-cause mortality in patients who received ICDs or CRT-Ds, without distinguishing the patients based on type of disease or device. Our analysis data showed that patients who received ICD or CRT-D therapy had an increasing tendency of all-cause mortality when accompanied by digitalis therapy. The mechanism of the increased all-cause mortality in ICD or CRT-D recipients by digitalis needs to be discussed. Digitalis has been widely used in HF and AF patients for decades and induces cardiac arrhythmias, such as atrial tachycardias with or without block, AV conduction disturbances, and ventricular tachyarrhythmias. Based on the proarrhythmic effect of digitalis and the increased rate of appropriate shocks in ICD or CRT-D recipients who are receiving digitalis therapy, we reasonably hypothesized that the side effects of digitalis result in an increased rate of appropriate device shocks, sequentially leading to shock-induced damage to the myocardium and a poor patient prognosis. Recent studies found a dysregulation of cardiac biomarkers, such as brain natriuretic peptide, and biomarkers of myocardial ischemia in patients who received ICD shocks, indicating that shocks may induce cardiomyocyte and cardiac dysfunction [37,38]. Moreover, animal experiments demonstrated that shocks triggered by ventricular arrhythmia could lead to intracellular calcium overload by phosphorylating membrane proteins that regulate intracellular calcium homeostasis and thus generate a vicious cycle of arrhythmia promotion [39]. Several other experimental studies have also found that electrical shocks could contribute to electroporation of the cellular membrane and cellular necrosis [40,41].Hence, the proarrhythmic effect of digitalis might be responsible for the increased mortality of ICD or CRT-D recipients.
By comparing the baseline characteristic of the nine studies that reported ICD and mortality, we found a higher proportion of included patients received ICD implantation for primary prevention. ICD implantation for primary prevention was for patients with an LVEF <35% and without a history of SCD or unexplained syncope; secondary prevention was for patients with sustained VT, SCD secondary to unstable VT or VF, or unexplained syncope in the setting of an LVEF <35%. Furthermore, digitalis tends to be used in advanced HF patients when physicians detect deterioration in patients resistant to initial treatment to improve cardiac function; the baseline characteristic (shown in Table 1) also showed a relatively lower LVEF in the digitalis therapy group compared with the non-digitalis therapy group. Hence, a possible explanation for increased mortality in ICD recipients might be that patients with implanted ICDs as a primary prevention may have a more complex condition and that digitalis tends to be used in advanced HF patients.
To investigate the impact of digitalis on patients receiving different device types, we conducted a subgroup analysis by dividing patients into one group receiving ICD therapy, one group receiving CRT-D therapy, and one group receiving ICD or CRT-D therapy. Our analysis found that digitalis increased the mortality of ICD recipients but did not increase the mortality in patients who received ICD or CRT-D therapy. CRT-Ds involve cardiac resynchronization therapy combined with defibrillator treatment. The difference between CRT-Ds and ICDs is that CRT-Ds have the function of biventricular pacing. The 2016 ESC guidelines recommended the use of CRT in patients with LVEF < 35% (NYHA III-IV) and QRS duration> 130 ms [42]. Previous studies have demonstrated that CRT could reduce the risk of life-threatening ventricular tachyarrhythmia, reverse cardiac remodeling, improve ventricular function, and reduce morbidity and mortality in advanced HF patients [43]. However, ICDs are recommended to reduce the risk of SCD and all-cause mortality in patients with mild HF (NYHA Class II–III). ICDs can only stop malignant arrhythmias and have no influence on the mortality or the rate of life-threatening ventricular tachyarrhythmia of HF patients. The effect of CRT-Ds on improving ventricular function may synergize with the positive inotropic effect to promote cardiac function in HF patients. The mechanism requires further verification in future studies.

4.3. Clinical Implications

Our results suggest that digitalis should be used with more caution in HF patients receiving device therapy. HF patients implanted with ICDs may not benefit from digitalis treatment; inversely, the use of digitalis may increase the rate of ICD-appropriate shocks, contributing to physiological myocardium injury [44], psychological anxiety [45,46], and increased all-cause mortality. Because our results showed that the mortality of CRT-D recipients under digitalis therapy did not increase, perhaps it is more appropriate for HF patients with CRT-D therapy to be treated with digitalis compared with those who receive ICD therapy.

4.4. Strengths and Limitations

Based on all available studies, we first demonstrated that our study suggests that digitalis might be associated with an increase in appropriate shocks, a reduced time to first appropriate shock in ICD or CRT-D recipients, and an increase in all-cause mortality in ICD recipients, but digitalis did not increase the mortality of CRT-D recipients. These findings provide a reference for physicians in clinical practice. Moreover, our study was performed in compliance with the PRISMA guidelines, which demonstrated that our meta-analysis is a relatively credible study.
However, there are some limitations in our study. First, the included studies were observational cohort studies rather than randomized controlled trials and a clear discrepancy in the sample sizes was noted based on the observational data. Second, our study only assessed all-cause mortality in recipients treated with digitalis and failed to assess cardiovascular mortality due to the lack of relevant data. This topic is worthy of further studies. Third, digitalis use was assessed at ICD or CRT-D implantation, but the administered medications were not mentioned during the follow-up time or at the time of death. For the lack of data, the effect of endogenous digitalis could not be explored. Fourth, due to the lack of data, we were unable to compare the impact of AF or HF disease on mortality in ICD/CRT-D recipients.

5. Conclusions

In summary, our study suggests that digitalis might be associated with an increase in appropriate shocks, a reduced time to first appropriate shock in ICD or CRT-D recipients, and an increase in all-cause mortality in ICD recipients. However, our results suggest that digitalis does not increase the all-cause mortality of CRT-D recipients, underscoring the significance of reassessing the effect of digitalis in the contemporary management of HF patients who receive ICD or CRT-D treatment.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm12041686/s1, Figure S1: (fixed effects model) Funnel plot of ICDs or CRT-Ds patients that received appropriate shocks. Figure S2: Sensitivity of the outcome (ICDs or CRT-Ds patients that received appropriate shocks). Figure S3: (random effects model) Funnel plot of ICDs or CRT-Ds recipients’ all-cause mortality. Figure S4: Sensitivity of the outcome (ICDs or CRT-Ds recipients’ all-cause mortality). Figure S5: Forest plot of the outcome of ICD or CRT-D recipients (digitalis versus digoxin therapy); Table S1: Quality assessment according to the Newcastle-Ottawa scale for nonrandomized studies. Table S2: Dosage or concentration of digitalis in the included articles. Table S3: Inclusion criteria of the ICDs or CRT-Ds recipients in the included studies. Table S4: PRISMA Checklist of the meta-analysis.

Author Contributions

W.Z. contributed to the acquisition of data, analysis and interpretation of data, drafting of the article, and final approval of the version to be published. H.L. contributed to the acquisition of data. L.F. and W.F. contributed to the interpretation of data. K.H. contributed to the conception and design of the study, analysis and interpretation of data, revising the article, and final approval of the version to be published. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC, 82030018).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations and Acronyms

ICDImplantable Cardioverter Defibrillator
CRT-DCardiac Resynchronization Therapy Defibrillator
HRsHazard Ratios
CIsConfidence Intervals
HFHeart Failure
AFAtrial Fibrillation
SCDSudden Cardiac Death
LVEFLeft Ventricular Ejection Fractions
VT/VFVentricular Tachycardia/Fibrillation
NOSNewcastle–Ottawa Scale
PRISMAPreferred Reporting Items for Systematic Reviews and Meta-Analyses
MeSHMedical Subject Headings
NYHANew York Heart Association
RevManReview Manager

References

  1. Gumprecht, J.; Domek, M.; Proietti, M.; Li, Y.G.; Asaad, N.; Rashed, W.; Alsheikh-Ali, A.; Zubaid, M.; Lip, G.Y.H. Compliance of Atrial Fibrillation Treatment with the Atrial Fibrillation Better Care (ABC) Pathway Improves the Clinical Outcomes in the Middle East Population: A Report from the Gulf Survey of Atrial Fibrillation Events (SAFE) Registry. J. Clin. Med. 2020, 9, 1286. [Google Scholar] [CrossRef] [PubMed]
  2. Ziff, O.J.; Kotecha, D. Digoxin: The good and the bad. Trends Cardiovasc. Med. 2016, 26, 585–595. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Yancy, C.W.; Jessup, M.; Bozkurt, B.; Butler, J.; Casey, D.E., Jr.; Drazner, M.H.; Fonarow, G.C.; Geraci, S.A.; Horwich, T.; Januzzi, J.L.; et al. 2013 ACCF/AHA guideline for the management of heart failure: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013, 128, 1810–1852. [Google Scholar] [CrossRef]
  4. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N. Engl. J. Med. 1997, 336, 525–533. [Google Scholar] [CrossRef]
  5. Heidenreich, P.A.; Bozkurt, B.; Aguilar, D.; Allen, L.A.; Byun, J.J.; Colvin, M.M.; Deswal, A.; Drazner, M.H.; Dunlay, S.M.; Evers, L.R.; 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. J. Am. Coll. Cardiol. 2022, 79, e263–e421. [Google Scholar]
  6. McDonagh, T.A.; Metra, M.; Adamo, M.; Gardner, R.S.; Baumbach, A.; Bohm, M.; Burri, H.; Butler, J.; Celutkiene, J.; Chioncel, O.; et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 2021, 42, 3599–3726. [Google Scholar] [CrossRef] [PubMed]
  7. Moss, A.J.; Zareba, W.; Hall, W.J.; Klein, H.; Wilber, D.J.; Cannom, D.S.; Daubert, J.P.; Higgins, S.L.; Brown, M.W.; Andrews, M.L.; et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N. Engl. J. Med. 2002, 346, 877–883. [Google Scholar] [CrossRef] [Green Version]
  8. Chen, Z.; Kotecha, T.; Crichton, S.; Shetty, A.; Sohal, M.; Arujuna, A.; Kirubakaran, S.; Bostock, J.; Cooklin, M.; O’Neill, M.; et al. Lower incidence of inappropriate shock therapy in patients with combined cardiac resynchronisation therapy defibrillators (CRT-D) compared with patients with non-CRT defibrillators (ICDs). Int. J. Clin. Pr. 2013, 67, 733–739. [Google Scholar] [CrossRef] [PubMed]
  9. Steffen, M.M.; Osborn, J.S.; Cutler, M.J. Cardiac Implantable Electronic Device Therapy: Permanent Pacemakers, Implantable Cardioverter Defibrillators, and Cardiac Resynchronization Devices. Med. Clin. N. Am. 2019, 103, 931–943. [Google Scholar] [CrossRef]
  10. Lee, A.Y.; Kutyifa, V.; Ruwald, M.H.; McNitt, S.; Polonsky, B.; Zareba, W.; Moss, A.J.; Ruwald, A.C. Digoxin therapy and associated clinical outcomes in the MADIT-CRT trial. Heart Rhythm. 2015, 12, 2010–2017. [Google Scholar] [CrossRef]
  11. Vamos, M.; Erath, J.W.; Hohnloser, S.H. Digoxin-associated mortality: A systematic review and meta-analysis of the literature. Eur. Heart J. 2015, 36, 1831–1838. [Google Scholar] [CrossRef] [Green Version]
  12. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; Group, P. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009, 6, e1000097. [Google Scholar] [CrossRef] [Green Version]
  13. Adelstein, E.; Schwartzman, D.; Jain, S.; Bazaz, R.; Saba, S. Effect of digoxin on shocks in cardiac resynchronization therapy-defibrillator patients with coronary artery disease. Am. J. Cardiol. 2014, 113, 970–975. [Google Scholar] [CrossRef]
  14. Balci, K.G.; Balci, M.M.; Şen, F.; Akboǧa, M.K.; Maden, O.; Selçuk, H.; Selçuk, T.; Balbay, Y.; Temizhan, A.; Aydoǧdu, S. The relation between digoxin and appropriate shocks in patients with ischemic heart failure and implantable cardioverter defibrillator. Anatol. J. Cardiol. 2016, 16, 52. [Google Scholar]
  15. Bilchick, K.C.; Stukenborg, G.J.; Kamath, S.; Cheng, A. Prediction of mortality in clinical practice for medicare patients undergoing defibrillator implantation for primary prevention of sudden cardiac death. J. Am. Coll. Cardiol. 2012, 60, 1647–1655. [Google Scholar] [CrossRef] [Green Version]
  16. Catanzaro, J.N.; Makaryus, A.N.; Sison, C.; Vavasis, C.; Donaldson, D.; Beldner, S.; Boal, B.; Jadonath, R. Clinical predictors of appropriate implantable-cardioverter defibrillator discharge. Pacing Clin. Electrophysiol. 2007, 30 (Suppl. 1), S120–S124. [Google Scholar] [CrossRef]
  17. Desai, H.; Aronow, W.S.; Tsai, F.S.; Ahn, C.; Lai, H.M.; Amin, H.; Gandhi, K.; Frishman, W.H.; Cohen, M.; Sorbera, C. Statins reduce appropriate cardioverter-defibrillator shocks and mortality in patients with heart failure and combined cardiac resynchronization and implantable cardioverter-defibrillator therapy. J. Cardiovasc. Pharm. 2009, 14, 176–179. [Google Scholar] [CrossRef] [PubMed]
  18. Desai, H.; Aronow, W.S.; Ahn, C.; Gandhi, K.; Hussain, S.; Lai, H.M.; Sharma, M.; Frishman, W.H.; Cohen, M.; Sorbera, C. Risk factors for appropriate cardioverter-defibrillator shocks, inappropriate cardioverter-defibrillator shocks, and time to mortality in 549 patients with heart failure. Am. J. Cardiol. 2010, 105, 1336–1338. [Google Scholar] [CrossRef]
  19. Erath, J.W.; Vamos, M.; Hohnloser, S.H. Effects of digitalis on mortality in a large cohort of implantable cardioverter defibrillator recipients: Results of a long-Term follow-up study in 1020 patients. Eur. Heart J.—Cardiovasc. Pharmacother. 2016, 2, 168–174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Ho, A.T.; Pai, S.M.; Timothy, P.; Pai, R.G. Effect of concomitant antiarrhythmic therapy on survival in patients with implantable cardioverter defibrillators. Pacing Clin. Electrophysiol. 2005, 28, 647–653. [Google Scholar] [CrossRef] [PubMed]
  21. Lee, D.S.; Hardy, J.; Yee, R.; Healey, J.S.; Birnie, D.; Simpson, C.S.; Crystal, E.; Mangat, I.; Nanthakumar, K.; Wang, X.; et al. Clinical Risk Stratification for Primary Prevention Implantable Cardioverter Defibrillators. Circ. Heart Fail. 2015, 8, 927–937. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Mina, G.S.; Acharya, M.; Shepherd, T.; Gobrial, G.; Tekeste, M.; Watti, H.; Bhandari, R.; Saini, A.; Reddy, P.; Dominic, P. Digoxin Is Associated With Increased Shock Events and Electrical Storms in Patients With Implantable Cardioverter Defibrillators. J. Cardiovasc. Pharmacol. Ther. 2018, 23, 142–148. [Google Scholar] [CrossRef] [PubMed]
  23. Morani, G.; Gasparini, M.; Zanon, F.; Casali, E.; Spotti, A.; Reggiani, A.; Bertaglia, E.; Solimene, F.; Molon, G.; Accogli, M.; et al. Cardiac resynchronization therapy-defibrillator improves long-term survival compared with cardiac resynchronization therapy-pacemaker in patients with a class IA indication for cardiac resynchronization therapy: Data from the Contak Italian Registry. Europace 2013, 15, 1273–1279. [Google Scholar] [CrossRef]
  24. Schupp, T.; Behnes, M.; Weiss, C.; Nienaber, C.; Reiser, L.; Bollow, A.; Taton, G.; Reichelt, T.; Ellguth, D.; Engelke, N.; et al. Digitalis therapy and risk of recurrent ventricular tachyarrhythmias and ICD therapies in atrial fibrillation and heart failure. Cardiology 2019, 142, 129–140. [Google Scholar] [CrossRef]
  25. Fauchier, L.; Clementy, N.; Marijon, E.; Defaye, P.; Piot, O.; Sadoul, N.; Gras, D.; Klug, D.; Algalarrondo, V.; Bordachar, P.; et al. Effect of digoxin on mortality in patients after primary prevention implantable cardioverter-defibrillator. A multicenter population-based cohort study. Heart Rhythm. 2016, 13, S257. [Google Scholar]
  26. Soliman, O.I.; Theuns, D.A.; van Dalen, B.M.; Vletter, W.B.; Nemes, A.; Jordaens, L.J.; Balk, A.H.; Ten Cate, F.J.; Geleijnse, M.L. Prediction of appropriate defibrillator therapy in heart failure patients treated with cardiac resynchronization therapy. Am. J. Cardiol. 2010, 105, 105–111. [Google Scholar] [CrossRef]
  27. Seegers, J.; Conen, D.; Jung, K.; Bergau, L.; Dorenkamp, M.; Lüthje, L.; Sohns, C.; Sossalla, S.T.; Fischer, T.H.; Hasenfuss, G.; et al. Sex difference in appropriate shocks but not mortality during long-term follow-up in patients with implantable cardioverter-defibrillators. Europace 2016, 18, 1194–1202. [Google Scholar] [CrossRef] [PubMed]
  28. Stein, K.M.; Mittal, S.; Gilliam, F.R.; Gilligan, D.M.; Zhong, Q.; Kraus, S.M.; Meyer, T.E. Predictors of early mortality in implantable cardioverter-defibrillator recipients. Europace 2009, 11, 734–740. [Google Scholar] [CrossRef]
  29. Thibodeau, J.B.; Pillarisetti, J.; Khumri, T.M.; Jones, P.G.; Main, M.L. Mortality Rates and Clinical Predictors of Reduced Survival After Cardioverter Defibrillator Implantation. Am. J. Cardiol. 2008, 101, 861–864. [Google Scholar] [CrossRef]
  30. Verstraelen, T.E.; van Barreveld, M.; van Dessel, P.; Boersma, L.V.A.; Delnoy, P.; Tuinenburg, A.E.; Theuns, D.; van der Voort, P.H.; Kimman, G.P.; Buskens, E.; et al. Development and external validation of prediction models to predict implantable cardioverter-defibrillator efficacy in primary prevention of sudden cardiac death. Europace 2021, 23, 887–897. [Google Scholar] [CrossRef]
  31. Bode, N.; Hochadel, M.; Andresen, D.; Zahn, R.; Spitzer, S.G.; Brachmann, J.; Stellbrink, C.; Jung, W.; Gonska, B.D.; Reinke, F.; et al. Cardiac glycosides are not associated with increased mortality or hospitalization rates in ICD and CRT-ICD patients after adjustment for baseline-characteristics at one-year follow-up: Results from the German DEVICE registry. Int. J. Cardiol. 2021, 338, 109–114. [Google Scholar] [CrossRef]
  32. Vandenberk, B.; Garweg, C.; Voros, G.; Flore, V.; Marynissen, T.; Sticherling, C.; Zabel, M.; Ector, J.; Willems, R. Changes in Implantation Patterns and Therapy Rates of Implantable Cardioverter Defibrillators over Time in Ischemic and Dilated Cardiomyopathy Patients. Pacing Clin. Electrophysiol. 2016, 39, 848–857. [Google Scholar] [CrossRef]
  33. Biton, Y.; Daimee, U.A.; Baman, J.R.; Kutyifa, V.; McNitt, S.; Polonsky, B.; Zareba, W.; Goldenberg, I. Prognostic Importance of Defibrillator-Appropriate Shocks and Antitachycardia Pacing in Patients With Mild Heart Failure. J. Am. Heart Assoc. 2019, 8, e010346. [Google Scholar] [CrossRef] [Green Version]
  34. Smith, T.W. Digitalis. Mechanisms of action and clinical use. N. Engl. J. Med. 1988, 318, 358–365. [Google Scholar] [PubMed]
  35. Gonano, L.A.; Sepulveda, M.; Rico, Y.; Kaetzel, M.; Valverde, C.A.; Dedman, J.; Mattiazzi, A.; Vila Petroff, M. Calcium-calmodulin kinase II mediates digitalis-induced arrhythmias. Circ. Arrhythm. Electrophysiol. 2011, 4, 947–957. [Google Scholar] [CrossRef] [Green Version]
  36. Ferrier, G.R. Digitalis arrhythmias: Role of oscillatory afterpotentials. Prog. Cardiovasc. Dis. 1977, 19, 459–474. [Google Scholar] [CrossRef] [PubMed]
  37. D’Onofrio, A.; Russo, V.; Bianchi, V.; Cavallaro, C.; Leonardi, S.; De Vivo, S.; Vecchione, F.; Rago, A.; Ammendola, E.; Tavoletta, V.; et al. Effects of defibrillation shock in patients implanted with a subcutaneous defibrillator: A biomarker study. Europace 2018, 20, f233–f239. [Google Scholar] [CrossRef]
  38. Francis, C.K.; Kuo, Y.H.; Azzam, I.; Selim, S.; Patel, N.; Beri, R.; Goldman, D.; Girgis, I.; Daniels, S. Brain natriuretic peptide and biomarkers of myocardial ischemia increase after defibrillation threshold testing. Pacing Clin. Electrophysiol. 2012, 35, 314–319. [Google Scholar] [CrossRef]
  39. Tsuji, Y.; Hojo, M.; Voigt, N.; El-Armouche, A.; Inden, Y.; Murohara, T.; Dobrev, D.; Nattel, S.; Kodama, I.; Kamiya, K. Ca(2+)-related signaling and protein phosphorylation abnormalities play central roles in a new experimental model of electrical storm. Circulation 2011, 123, 2192–2203. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  40. Pakhomov, A.G.; Shevin, R.; White, J.A.; Kolb, J.F.; Pakhomova, O.N.; Joshi, R.P.; Schoenbach, K.H. Membrane permeabilization and cell damage by ultrashort electric field shocks. Arch. Biochem. Biophys. 2007, 465, 109–118. [Google Scholar] [CrossRef]
  41. Lee, R.C.; Zhang D and Hannig, J. Biophysical injury mechanisms in electrical shock trauma. Annu. Rev. Biomed. Eng. 2000, 2, 477–509. [Google Scholar] [CrossRef]
  42. Ponikowski, P.; Voors, A.A.; Anker, S.D.; Bueno, H.; Cleland, J.G.; Coats, A.J.; Falk, V.; Gonzalez-Juanatey, J.R.; Harjola, V.P.; Jankowska, E.A.; 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. J. Heart Fail. 2016, 18, 891–975. [Google Scholar] [PubMed]
  43. Barsheshet, A.; Wang, P.J.; Moss, A.J.; Solomon, S.D.; Al-Ahmad, A.; McNitt, S.; Foster, E.; Huang, D.T.; Klein, H.U.; Zareba, W.; et al. Reverse remodeling and the risk of ventricular tachyarrhythmias in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy). J. Am. Coll. Cardiol. 2011, 57, 2416–2423. [Google Scholar] [CrossRef] [PubMed]
  44. Hasdemir, C.; Shah, N.; Rao, A.P.; Acosta, H.; Matsudaira, K.; Neas, B.R.; Reynolds, D.W.; Po, S.; Lazzara, R.; Beckman, K.J. Analysis of troponin I levels after spontaneous implantable cardioverter defibrillator shocks. J. Cardiovasc. Electrophysiol. 2002, 13, 144–150. [Google Scholar] [CrossRef]
  45. Pedersen, S.S.; den Broek, K.C.; Theuns, D.A.; Erdman, R.A.; Alings, M.; Meijer, A.; Jordaens, L.; Denollet, J. Risk of chronic anxiety in implantable defibrillator patients: A multi-center study. Int. J. Cardiol. 2011, 147, 420–423. [Google Scholar] [CrossRef]
  46. Passman, R.; Subacius, H.; Ruo, B.; Schaechter, A.; Howard, A.; Sears, S.F.; Kadish, A. Implantable cardioverter defibrillators and quality of life: Results from the defibrillators in nonischemic cardiomyopathy treatment evaluation study. Arch. Intern Med. 2007, 167, 2226–2232. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Jcm 12 01686 g001 550
Figure 1. Flowchart of study selection.
Figure 1. Flowchart of study selection.
Jcm 12 01686 g001
Jcm 12 01686 g002 550
Figure 2. Pooled risk of shocks. Given the low heterogeneity, a fixed effects model was used. (A) Forest plot of the association between digitalis and risk of appropriate shocks. (B) Forest plot assessing the time to first appropriate shock in ICD or CRT-D recipients administered digitalis [10,13,14,16,18,21,22,24,26,30,32].
Figure 2. Pooled risk of shocks. Given the low heterogeneity, a fixed effects model was used. (A) Forest plot of the association between digitalis and risk of appropriate shocks. (B) Forest plot assessing the time to first appropriate shock in ICD or CRT-D recipients administered digitalis [10,13,14,16,18,21,22,24,26,30,32].
Jcm 12 01686 g002
Jcm 12 01686 g003 550
Figure 3. Pooled risk of all-cause mortality. Given the high heterogeneity, a random effects model was used. (A) Forest plot assessing all-cause mortality in recipients treated with digitalis. The studies were categorized as those including HF patients and those including general people without mentioning the exact disease. (B) Forest plot depicting the all-cause mortality among ICD recipients, CRT-D recipients, and ICD or CRT-D recipients [10,13,15,17,18,19,20,23,25,27,28,29,31,32].
Figure 3. Pooled risk of all-cause mortality. Given the high heterogeneity, a random effects model was used. (A) Forest plot assessing all-cause mortality in recipients treated with digitalis. The studies were categorized as those including HF patients and those including general people without mentioning the exact disease. (B) Forest plot depicting the all-cause mortality among ICD recipients, CRT-D recipients, and ICD or CRT-D recipients [10,13,15,17,18,19,20,23,25,27,28,29,31,32].
Jcm 12 01686 g003
Table
Table 1. Basic Characteristics of Studies Included in the Meta-Analysis.
Table 1. Basic Characteristics of Studies Included in the Meta-Analysis.
Study (First Author, Year)Study DesignRegionNumber of Participants (N)Follow-Up Duration (m)Age (year)Male (%)AF (%)LVEFQRS (ms)Prevention TypesDiseaseMedicineTherapyOutcome Events
Adelstein, 2014 [13]Prospective studyUSADigitalis: 162; non-digitalis: 18848 ± 32Digitalis: 69 ± 10; non-digitalis: 71 ± 10Digitalis:77; non-digitalis: 84Digitalis: 32; non-digitalis: 26Digitalis: 21 ± 6; non-digitalis: 23 ± 6Digitalis: 165 ± 26; non-digitalis: 160 ± 24PrimaryHFDigoxinCRT-DDeath/AS/time to first AS
Balci, 2016 [14]Retrospective studyTurkey139NANANANANANANAHFDigoxinICDAS
Bilchick, 2012 [15]Prospective studyUSA17,99152.8 (median)72.5 (median)38.9NANANAPrimaryHFDigoxinICDDeath
Bode, 2021 [31]Prospective studyGermanyICD:
digitalis: 525;
non-digitalis: 3257		1 yICD:
digitalis: 65.7 ± 12.1; non-digitalis: 64 ± 13.7		ICD: digitalis: 85.3;
non-digitalis: 81.4		NALVEF < 35%:
digitalis: 85.7%;
non-digitalis: 66.3%		QRS ≥ 130 ms:
digitalis: 25.2%;
non-digitalis: 18.4%		PrimaryAF/
HF		Cardiac glycosidesICD/CRT-DDeath
Catanzaro, 2007 [16]Retrospective studyUSA59110.9 ± 13.867.9 ± 13.080.2Male: 5.9; female: 8.6LVEF < 35%:
male: 61.7%; female: 52.4%		NANANADigitalisICDTime to first AS
Desai, 2009 [17]Retrospective studyUSA20941.4 ± 21.874 (median)79.9NANANANAHFDigoxinICDDeath
Desai, 2010 [18]Retrospective studyUSA54934 (mean)Inappropriate shock: 75 ± 6; non-inappropriate shocks: 73 ± 10Inappropriate shock: 77; non-inappropriate shocks: 79Inappropriate shock:41; non-inappropriate shocks: 9Inappropriate shock: 28 ± 8; non-inappropriate shocks: 29 ± 7Inappropriate shock: 117 ± 21; non-inappropriate shocks: 118 ± 19NAHFDigoxinICDAS/death
Erath, 2016 [19]Retrospective studyGermanyDigitalis: 438; non-digitalis: 58237 (median)Digitalis: 63;
non-digitalis: 62		Digitalis: 79;
non-digitalis: 80		Digitalis: 21;
non-digitalis: 10		Digitalis: 26;
non-digitalis: 38		QRS ≥ 120 ms:
digitalis: 47%;
non-digitalis: 33%		Primary: digoxin: 57%; non-digoxin: 57%
secondary: digoxin: 43%; non-digoxin: 43%		NADigitalisICDDeath
Fauchier, 2016 [25]Retrospective studyFranceDigoxin: 225;
non-digoxin: 3759		3.1 ± 2 yDigoxin: 63 ± 11; non-digoxin: 63 ± 11NADigoxin: 51;
non-digoxin: 20		Digoxin: 24;
non-digoxin: 27		NAPrimaryAF/
HF		DigoxinICDDeath
Ho, 2005 [20]Retrospective studyUSA36052.8 ± 44.462 ± 1380NA33 ± 17NANANADigoxinICDDeath
Lee.A, 2015 [10]Retrospective studyUSADigoxin: 468;
non-digoxin: 1352		NADigoxin: 62.8 ± 11.9;
non-digoxin: 65 ± 10.3		Digoxin: 65;
non-digoxin: 79		Digoxin: 12;
non-digoxin: 12		Digoxin: 23.2 ± 5.5;
non-digoxin: 24 ± 5.2		Digoxin: 160 ± 21.3;
non-digoxin: 157.2 ± 19.1		NAHFDigoxinICD/CRT-DAS/death
Lee.D, 2015 [21]Prospective studyCanada34455918 person-years66 (58,30)80NANANAPrimaryHFDigoxinICDAS
Mina, 2018 [22]Retrospective studyUSADigoxin: 55;
non-digoxin: 147		NADigoxin: 60.18 ± 12.23;
non-digoxin: 61.44 ± 9.44		Digoxin: 61.8;
non-digoxin: 64.6		Digoxin: 10.9;
non-digoxin: 6.1		Digoxin: 27.86 ± 13.03;
non-digoxin: 27.38 ± 11.18		QRS > 120 ms:
digoxin: 31.6%; non-digoxin: 28.8%		Primary: digoxin: 90.9%; non-Digoxin: 91.2%
Secondary: digoxin: 9.1%; non-digoxin: 8.8%		AF/
HF		DigoxinICDShocks
Morani, 2013 [23]Retrospective studyItaly37455 (median)69 ± 1080NA27 ± 5168 ± 31Primary: 84%; Secondary: 16%HFDigoxinCRT-DDeath
Schupp, 2019 [24]Retrospective studyGermanyDigitalis: 104; non-digitalis: 29060 (median)Digitalis: 68;
non-digitalis: 66		Digitalis: 80;
non-digitalis: 82		Digitalis: 57;
non-digitalis: 39		LVEF < 35%:
digitalis: 73%;
non-digitalis: 62%		Digitalis: 109 ± 8;
non-digitalis: 117 ± 5		Primary: digoxin: 45%; non-digoxin: 46%
Secondary: digoxin: 55%; non-digoxin: 54%		AF/
HF		DigitalisICDAppropriate device therapy
Seegers, 2016 [27]Retrospective studyGermany115158.8 ± 32.4Male: 65 ± 12;
female: 62 ± 15		81.2NAMale: 29 ± 11; female: 34 ± 13Male: 123 ± 32; female: 112 ± 30Primary: female: 53%; male: 55%;
Secondary: female: 47%; male: 45%		NADigitalisICDDeath
Soliman, 2010 [26]Retrospective studyNetherlands169654 ± 394 days60 ± 1274NA22 ± 4166 ± 30PrimaryHFDigitalisCRT-DAS
Stein, 2009 [28]Prospective studyUSA170312.5 (median)67 ± 12 8226LVEF < 20:10%
20 ≤ LVEF < 30:30%
30 ≤ LVEF < 40:33%
40 ≤ LVEF: 24%		NAPrimary: 48%; secondary: 52%NADigitalisICDDeath
Thibodeau, 2008 [29]Retrospective studyUSA28640 ± 21.764.7 ± 13.482.9NA10 ≤ LVEF < 25:37.1%
25 ≤ LVEF < 35:28.8%
35 ≤ LVEF < 45:18.7%
45 ≤ LVEF < 70:15.5%		NAPrimary: 39.5%;
secondary: 60.1%;
unknown: 0.3%		NADigoxinICDDeath
Vandenberk, 2016 [32]Retrospective studyUSA7275.2 ± 4.1 y62.5 ± 11.784.98.132.4 ± 12.4131 ± 34Primary: 56%; secondary: 44%ICM or NICMDigitalisICDAS/Death
Verstraelen, 2021 [30]Prospective studyEnglandDO-IT:1443;
EU-CERT-ICD:1450		2.4 yDO-IT: 65.9;
EU-CERT-ICD: 61.9		DO-IT: 72;
EU-CERT-ICD: 83		DO-IT: 31;
EU-CERT-ICD: 25		DO-IT: 26.1;
EU-CERT-ICD: 27.5		QRS > 150 ms
DO-IT: 23%;
EU-CERT-ICD: 2%		PrimaryHFDigoxinICD/CRT-DAS
Abbreviations: NA—not available; HF—heart failure; CRT-D—cardiac resynchronization therapy defibrillator; ICD—implantable cardioverter-defibrillator; AS—appropriate shocks; AF—atrial fibrillation; LVEF—left ventricular ejection fraction; ICM—ischemic cardiomyopathy; NICM—non-ICM; m—month; y—year.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Zhuo, W.; Liu, H.; Fu, L.; Fan, W.; Hong, K. Effect of Digitalis on ICD or CRT-D Recipients: A Systematic Review and Meta-Analysis. J. Clin. Med. 2023, 12, 1686. https://doi.org/10.3390/jcm12041686

AMA Style

Zhuo W, Liu H, Fu L, Fan W, Hong K. Effect of Digitalis on ICD or CRT-D Recipients: A Systematic Review and Meta-Analysis. Journal of Clinical Medicine. 2023; 12(4):1686. https://doi.org/10.3390/jcm12041686

Chicago/Turabian Style

Zhuo, Wen, Hualong Liu, Linghua Fu, Weiguo Fan, and Kui Hong. 2023. "Effect of Digitalis on ICD or CRT-D Recipients: A Systematic Review and Meta-Analysis" Journal of Clinical Medicine 12, no. 4: 1686. https://doi.org/10.3390/jcm12041686

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop