Author + information
- Received September 25, 2017
- Revision received February 20, 2018
- Accepted February 27, 2018
- Published online August 27, 2018.
- Gabriel A. Hernandez, MDa,∗ (, )
- Vanessa Blumer, MDb,
- Luis Arcay, MDb,
- Jorge Monge, MDb,
- Juan F. Viles-Gonzalez, MDc,
- JoAnn Lindenfeld, MDa,
- Jeffrey J. Goldberger, MDd and
- Sandra Chaparro, MDd
- aDivision of Advanced Heart Failure and Transplant Cardiology, Vanderbilt University Medical Center, Nashville, Tennessee
- bInternal Medicine, Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida
- cCardiovascular Division, Department of Medicine, Tulane University, New Orleans, Louisiana
- dCardiovascular Division, Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida
- ↵∗Address for correspondence:
Dr. Gabriel A. Hernandez, Division of Advanced Heart Failure and Transplant Cardiology, Vanderbilt University Medical Center, 1215 21st Avenue South, Medical Center East Office 5037, Nashville, Tennessee 37232.
Objectives The purpose of this study was to evaluate outcomes after cardiac resynchronization therapy (CRT) in inotrope-dependent patients with heart failure (HF) to ascertain the viability of CRT in these patients.
Background During the last decade, significant numbers of trials have demonstrated the beneficial effect of CRT in the treatment of patients with HF and systolic dysfunction, prolonged QRS complex duration, and New York Heart Association functional class III or IV. However, it is currently undetermined whether CRT may benefit patients who require inotropic support.
Methods The authors systematically searched Medline, Embase, Scopus, and the Cochrane Library through March 2017 for studies evaluating outcomes after CRT in inotrope-dependent patients with HF. The study analyzed 8 studies including 151 patients. Most of the patients were in New York Heart Association functional class IV (80.1%), and all had severe systolic HF, with a left ventricular ejection fraction <30% and a significant intraventricular conduction delay in their surface electrocardiogram (QRS complex duration >130 ms).
Results The pooled analysis demonstrated that 93% of the reported patients (95% confidence interval: 86% to 100%) were weaned from inotropic support after CRT, and the overall 12-month survival rate was 69% (95% confidence interval: 56% to 83%).
Conclusions This study suggests that rescue CRT may be considered a viable therapeutic option in inotrope-dependent patients with HF. In these patients, rescue CRT may allow them to be weaned from inotropic therapy, improve their quality of life, and decrease the rate of mortality; furthermore, rescue CRT may serve as a possible bridge to cardiac transplantation or left ventricular assist device therapy.
- cardiac resynchronization therapy
- heart failure
- New York Heart Association functional class IV
Despite multiple advances in the field of heart failure (HF), the mortality rate of patients with advanced disease continues to be exceptionally high (1,2). Among these patients, those with end-stage HF requiring inotropic support likely have the worse prognosis with medical management (3,4).
Heart transplantation remains the gold standard therapy for patients with end-stage disease; however, this option is constrained by limited donor supply. During the past decade, left ventricular assist devices (LVADs) have emerged as treatment options for those patients waiting for transplant, as destination therapy and, in a smaller group, as a bridge to recovery (5). LVAD technology offers survival benefit and improved quality of life when compared with medical therapy alone (6–8), but it does come at the risk of well-described complications, financial cost, and some contraindications (9–14).
Along with this, significant numbers of trials have demonstrated the beneficial effect of cardiac resynchronization therapy (CRT) in the treatment of patients with HF by reducing morbidity and mortality in those patients with systolic dysfunction, prolonged QRS complex duration, and New York Heart Association (NYHA) functional class III or IV symptoms, when combined with optimal pharmacotherapy (15). However, during initial trials, NYHA functional class IV patients not only were underrepresented but also were considered not to be CRT candidates because of their poor estimated survival (16). Hence, it is currently undetermined whether CRT may benefit these patients. On the basis of a review of published reports, we sought to identify the possible benefits of this therapy in end-stage inotrope-dependent patients.
We undertook this systematic review according to recommendations of the Cochrane Collaboration and in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement (17).
Search strategy for identification of relevant studies
We systematically searched Medline, Embase, Scopus, and the Cochrane Library through March 2017 for full papers that evaluated outcomes after CRT in inotrope-dependent patients with HF. No language limits were used. Databases were searched with the following terms: “end-stage heart failure,” “catecholamine-dependent overt heart failure,” “inotrope-dependent heart failure,” “advanced heart failure,” “New York Heart Association class IV,” “NYHA class IV.” These terms were searched individually with “cardiac resynchronization therapy” OR “CRT” OR “biventricular device,” combined by the boolean term “AND.” This strategy was used both as Medical Subject Headings (MeSH) terms if available and as free text. Reference lists from all included studies were manually searched for additional studies.
Selection criteria and data extraction
To be eligible, studies were required to meet the following inclusion criteria: 1) patients had to be dependent on inotropic support at the time of CRT implantation; 2) if the study included other patients, outcomes had to be specifically reported on the inotrope-dependent patients; 3) patients included had to be more than 18 years of age; and 4) papers included had to state a clear definition of “inotrope-dependence” or “inability to wean.” In most of the included studies, inotrope dependence was defined as the inability to wean or withdraw inotropic support without noting clinical or biochemical parameters suggestive of low cardiac output. Alternatively, in some studies, “inotrope-dependence” was endorsed by the treating cardiologist who considered that inotropic therapy could not be safely withdrawn. Both definitions were acceptable for inclusion in our analysis. If the paper did not include a specific definition, the corresponding authors were contacted to further query the selection criteria used. We excluded studies containing patients with advanced HF that were not clearly dependent on inotropic support, and if the outcomes were not evidently distinguished in the inotrope-dependent population.
Three investigators independently reviewed the study titles, abstracts, and full-length articles to determine study inclusion and exclusion. These reviewers also independently abstracted the study design, patients’ baseline characteristics, and relevant outcomes. An electronic data form was used to compile abstracted information. Differences were adjudicated by consensus and by the senior author, when necessary.
A random-effects meta-analysis was performed using pooled proportions, and heterogeneity was examined using I2 statistics to determine the overall mortality rate of patients on inotropic support after CRT implantation. In secondary analysis, specific outcomes associated with CRT were studied in a similar manner. Outcomes of interest included proportion of patients off inotropic support and proportion of patients who improved their NYHA functional class after CRT. When available, we analyzed survival estimates at 1 year, in which possible endpoints were all-cause mortality, LVAD implantation, or heart transplantation. A Kaplan-Meier curve was generated to describe overall survival and survival free of LVAD. For the statistical analyses, we used Stata software version 13 (StataCorp., College Station, Texas).
Study search and general characteristics
The search retrieved 2,358 citations. Of these, 1,652 were duplicates, and 654 were not related to the study question on the basis of title and abstract review. A total of 52 studies were fully screened and assessed for potential inclusion. Of these 52 studies, 8 fulfilled all criteria for inclusion (Figure 1) (18–25). All included manuscripts were retrospective observational analyses. Details of the included studies and baseline characteristics of the study patients are listed in Table 1.
Overall, 151 patients were systematically reviewed and included for analysis. These patients were followed for 877 ± 620 days and were mostly male (80%), with a mean age of 64 years. The patients included were more likely to have ischemic cardiomyopathy (64%) than nonischemic cardiomyopathy (36%) as the etiology of HF. Most patients were in NYHA functional class IV (80.1%), and all had a left ventricular ejection fraction <30% and a significant intraventricular conduction delay on their surface electrocardiogram (QRS complex duration >130 ms). Although all of the studies reported the QRS complex duration, only 5 of 8 studies reported the QRS complex configuration. The most common configuration was left bundle branch block (n = 35) followed by intraventricular conduction delay (n = 15), paced rhythm (n = 9), and right bundle branch block (n = 6). When reported, most patients had received CRT with a defibrillator (96.8%; n = 95).
Seven of the 8 included studies reported their inotrope weaning success. Our pooled analysis of those studies demonstrated that 93% of the reported patients were weaned from inotropic support after CRT implantation (95% confidence interval [CI]: 86% to 100%). The overall heterogeneity, examined through I2 statistics, of the proportion of patients remaining off inotropic support was low, estimated at 36.86% (Figure 2).
Six studies reported the NYHA functional class change after CRT. In this regard, 2% improved to NYHA functional class I (95% CI: 2% to 6%), 36% of these patients improved to NYHA functional class II (95% CI: 15% to 57%), 43% improved to NYHA functional class III (95% CI: 10% to 76%), and only 10% remained in NYHA functional class IV (95% CI: 3% to 18%) (Figures 3A to 3C). Nakajima et al. (24) reported 3 deaths within the first 3 months and 3 patients who could not be withdrawn from inotropic support; these patients have not been included in Figures 3A to 3C. All of the included studies reported 12-month survival with an overall survival rate of 69% (95% CI: 56% to 83%) (Figure 4). Furthermore, during the first year of follow-up, 6 patients had undergone heart transplantation (included in the year-survival), and 53 patients either had died or had undergone LVAD implantation and were included in the year-mortality; these patients were included in the survival free of LVAD Kaplan-Meier curve. None of the 6 patients who underwent heart transplantation during the first year were bridged with an LVAD.
Additionally, 6 studies reported periprocedural complications, which are summarized in Online Table 1. No fatal events were reported, and a total of 9 nonfatal events (7.82%) were captured out of 115 patients, most commonly device infection (1 confirmed infection and 2 possible infections) and contrast-induced nephropathy.
Funnel plots were constructed to assess publication bias for key study outcomes (Online Figures 1A and 1B). Egger’s test was used to assess for publication bias because conventional funnel plots have been shown to be inaccurate for meta-analyses of proportion studies (26). We found no significant publication bias as estimated by Egger’s test for the proportion of patients weaned from inotropic support (p = 0.06) and overall survival at 12 months (p = 0.20); however, this assessment may be limited by the small number of studies included in the analysis.
Our analysis suggests that resynchronization therapy may enable inotrope-dependent patients to be weaned from inotropic support after CRT implantation and achieve significant improvement in symptoms and overall survival.
The role of CRT in NYHA functional class IV patients remained uncertain until Lindenfeld et al. (27) examined the outcomes of NYHA functional class IV ambulatory patients (non–inotrope dependent) enrolled in the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial to assess the potential benefits of CRT and CRT with a defibrillator. Their analysis suggested that CRT and CRT with a defibrillator significantly improved time to all-cause mortality and hospitalizations in NYHA functional class IV patients, with a trend for improved mortality (27). Later, Herweg and Barold (28) commented on published reports that included NYHA functional class IV patients who were receiving intravenous inotropic therapy at the time of CRT implantation. Their analysis proposed that CRT could provide survival benefit in even the sickest end-stage patients and suggested that CRT should not be automatically dismissed as contraindicated in patients with NYHA functional class IV HF who are receiving inotropic support (28).
Heart transplantation remains the treatment of choice in patients with advanced refractory HF. Nevertheless, many patients are ineligible for cardiac transplantation because of advanced age, burden of comorbidities, or limited donor organ supply (5). Additionally, patients with poor social support do not qualify for LVAD placement in most centers. The impending high costs related to LVAD implantation also limit the widespread use of this therapy. For example, 3 of the 8 included studies (18,22,29) enrolled only patients (total of 45 patients) described as being ineligible for heart transplantation or LVAD (age and comorbidities being the most common contraindications), and of those, 60% (n = 27) survived at 1 year. These selected patients who are not candidates for heart replacement therapies could still benefit from rescue CRT, rather than remaining on inotropes as destination therapy.
Given the lack of randomized trials, comparing these patients with a control group can be challenging; therefore, some studies have compared this these patients with the medical arm of the REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure) study, given that these patients had similar baseline characteristics with regard to disease severity (19). At a 1-year follow-up, there was a 75% mortality rate in the medical treatment group of the REMATCH study (6). In our study, following CRT implantation, there was an overall mortality rate of 31% at 1 year. Thus, there may be a substantial mortality reduction when rescue CRT is used in inotrope-dependent patients with HF when compared with medical treatment alone. When comparing our study patients with the medical arm of the REMATCH study, mortality at 1 year was reduced from 75% to 31%. Furthermore, our cohort had better outcomes than the LVAD arm when our Kaplan-Meier curves were superimposed (Figure 5A). However, it is worth noting that REMATCH used a first-generation pulsatile LVAD on patients who were transplant ineligible, thus implying a sicker group of patients than ours (two-thirds of them receiving inotropic support). Nonetheless, when comparing only the 3 studies that included transplant-ineligible patients, the survival rate in the rescue CRT group remained higher (60% vs. 52%).
Although our results are promising, the 1-year survival rate for patients with continuous-flow LVADs is higher than for those inotrope-dependent patients who undergo CRT implantation (7,30). However, the rates of complications related to LVADs are higher than the rates of complications with CRT. In REMATCH, within 3 months of implantation, the probability of LVAD infection was 28%. Within 6 months, the frequency of bleeding was 42%, and the probability of device failure was 35% at 24 months (6). In the ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patient) study (7), surgical and nonsurgical bleeding accounted for 65% of LVAD events. The composite adverse event rate for bleeding, driveline infection, pump thrombosis, stroke, ventricular arrhythmias, and worsening HF was 1.89 events per patient-year in the LVAD group versus 0.83 in the medical therapy group. Additionally, more LVAD-treated patients (80%) than the control group (62%) had rehospitalizations within 1 year of enrollment. According to the 7th INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) annual report, from 2012 to 2014, there were 4,420 bleeding events (per 100 patient-months), followed by 4,132 infections and 916 strokes in the first 12 months after implantation of a continuous-flow LVAD (5). In the recent multicenter MOMENTUM 3 (MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) study, a newer generation of continuous-flow magnetically levitated centrifugal-flow pumps (HeartMate 3) showed improvement in clinical outcomes at 6 months resulting from reduction in the rate of reoperation for pump malfunction; however, researchers found no significant between-group differences in the rates of death or in other adverse outcomes such as disabling stroke (31). By contrast, the safety of CRT has been evaluated in a meta-analysis of 9,677 patients with CRT or CRT with a defibrillator and showed similar safety outcomes in both devices (15). In CRT alone, the implant success rate was 93.0%, with a 4.3% rate of peri-implantation mechanical complications and a 0.3% rate of peri-implant deaths. At 6 months of CRT alone, devices malfunctioned in 5% of patients, and 1.8% of patients required hospitalization for infections in the implant site.
Comparing our Kaplan-Meier survival curve with ENDURANCE (The HeartWare Ventricular Assist System as Destination Therapy of Advanced Heart Failure: the ENDURANCE Trial) (30), a recent destination therapy trial comparing axial with centrifugal continuous-flow devices, is also noteworthy; most of these patients had an INTERMACS profile of 1 to 3 (>70%), and although there was no medical arm of the trial, the year survival free of disabling stroke or pump replacement for either type of pump was roughly 71%, which is close to our 1-year survival free of LVAD (Figure 5B). Finally, to be able to compare our cohort’s outcomes with a more stable study group, we compared with to the ROADMAP study (7), which included patients in NYHA functional class III or IV who were not dependent on intravenous inotropic support. This trial showed that 1-year survival with improved functional status was higher in patients with continuous-flow LVADs when compared with optimal medical therapy including CRT (80% vs. 63%), with the benefit extending now to 2 years (32). Interestingly, when overlapping our survival curve (Figure 5C), it resembles that of the medical therapy group. This comparison favors our discussion in that rescue CRT in inotrope-dependent patients improves hemodynamic parameters to resemble those of INTERMACS >4 and may even translate into better post-operative results if rescue CRT is attempted before LVAD implantation.
Ultimately, these strategies may need to be directly compared in a clinical trial. At present, there are no randomized trials evaluating the benefit of CRT in patients who require inotropic support. Furthermore, scientific guidelines have not specifically addressed the role of CRT in these patients (33).
Our analysis has limitations, most of them inherent to the study design, retrospective nature of the included studies, and lack of control group. Most of the articles assessed for eligibility reported positive outcomes, thus raising the possibility of publication bias. Notwithstanding, we found no significant publication bias as estimated by Egger's test for the proportion of patients weaned off inotropic support and overall survival at 12 months. Additionally, nonuniform and unspecified enrollment criteria may confound the precise delineation and identification of true responders. For example, 64% of the reported patients in our study had ischemic cardiomyopathy, and additional clinical parameters such as scar burden and areas of delayed activation were lacking.
Furthermore, the duration of HF and exposure to ideal medical therapy are crucial because it is possible that patients who had a shorter duration of HF or who had not been exposed to optimal medical therapy at the time of CRT implantation may have higher chances of response once guideline-directed therapies are initiated.
The prognosis of inotrope-dependent patients with HF remains overwhelmingly poor in the absence of heart replacement therapies. Our study suggests that rescue CRT may be considered a viable therapeutic option in inotrope-dependent patients with HF. In these patients, CRT could allow them to be weaned from inotropic therapy, improve their quality of life, and decrease the rate of mortality; furthermore, it may serve as a possible bridge to heart transplantation or LVAD. Our results are encouraging and should stimulate further research with larger, randomized, prospective studies to identify factors that predict a beneficial response to resynchronization therapy.
COMPETENCY IN MEDICAL KNOWLEDGE: The mortality rate of patients with advanced HF continues to be exceptionally high, and patients with end-stage HF requiring inotropic support likely have the worse prognosis with medical management. Being able to set forward efforts to explore CRT as an option to wean these patients from their inotropic therapy, improve their quality of life, and decrease the rate of mortality is beyond encouraging.
TRANSLATIONAL OUTLOOK: CRT may be a plausible therapeutic option in selected patients with end-stage inotrope-dependent HF who are not eligible for heart transplantation or LVAD therapy. Additional studies are needed to identify CRT responders among patients with end-stage inotrope-dependent HF and to characterize further the rationale for this potential response.
Dr. Lindenfeld is a consultant for Boston Scientific, Novartis, Edwards, Abbott, Relypsa, Resmed, and VWave; and has received grants from the National Institutes of Health, the American Heart Association, Novartis, and AstraZeneca. Dr. Goldberger is the Director of the Path to Improved Risk Stratification, NFP, a not-for-profit organization on risk stratification for sudden cardiac death that has received unrestricted educational grants from Boston Scientific, Gilead, GE Medical, Medtronic, and St. Jude. Dr. Chaparro has received research grants from Abbott and Medtronic; and is a consultant for Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Drs. Hernandez and Blumer contributed equally to this work and are joint first authors.
John R. Teerlink, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- confidence interval
- cardiac resynchronization therapy
- heart failure
- Interagency Registry for Mechanically Assisted Circulatory Support
- left ventricular assist device
- New York Heart Association
- Received September 25, 2017.
- Revision received February 20, 2018.
- Accepted February 27, 2018.
- 2018 American College of Cardiology Foundation
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