J A C C : H E A R T F A I L U R E VO L . 6 , N O . 9 , 2 0 1 8

ª 2 0 1 8 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N

P U B L I S H E D B Y E L S E V I E R

FOCUS ISSUE: ADVANCED HEART FAILURE:INOTROPES AND MECHANICAL SUPPORT

CLINICAL RESEARCH

Cardiac Resynchronization Therapyin Inotrope-DependentHeart Failure PatientsA Systematic Review and Meta-Analysis

Gabriel A. Hernandez, MD,a Vanessa Blumer, MD,b Luis Arcay, MD,b Jorge Monge, MD,b Juan F. Viles-Gonzalez, MD,c

JoAnn Lindenfeld, MD,a Jeffrey J. Goldberger, MD,d Sandra Chaparro, MDd

ABSTRACT

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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

functionalclass III or IV.However, it is currentlyundeterminedwhetherCRTmaybenefitpatientswhorequire 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. (J Am Coll Cardiol HF 2018;6:734–42)

© 2018 by the American College of Cardiology Foundation.

N 2213-1779/$36.00 https://doi.org/10.1016/j.jchf.2018.02.016

m the aDivision of Advanced Heart Failure and Transplant Cardiology, Vanderbilt University Medical Center, Nashville,

nnessee; bInternal Medicine, Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida;

rdiovascular Division, Department of Medicine, Tulane University, New Orleans, Louisiana; and the dCardiovascular Division,

partment of Medicine, Miller School of Medicine, University of Miami, Miami, Florida. Dr. Lindenfeld is a consultant for Boston

entific, Novartis, Edwards, Abbott, Relypsa, Resmed, and VWave; and has received grants from the National Institutes of

alth, the American Heart Association, Novartis, and AstraZeneca. Dr. Goldberger is the Director of the Path to Improved Risk

atification, NFP, a not-for-profit organization on risk stratification for sudden cardiac death that has received unrestricted

ucational grants from Boston Scientific, Gilead, GE Medical, Medtronic, and St. Jude. Dr. Chaparro has received research grants

m Abbott and Medtronic; and is a consultant for Abbott. All other authors have reported that they have no relationships

evant to the contents of this paper to disclose. Drs. Hernandez and Blumer contributed equally to this work and are joint first

thors. John R. Teerlink, MD, served as Guest Editor for this paper.

nuscript received September 25, 2017; revised manuscript received February 20, 2018, accepted February 27, 2018.

AB BR E V I A T I O N S

AND ACRONYM S

CI = confidence interval

CRT = cardiac

resynchronization therapy

HF = heart failure

INTERMACS = Interagency

Registry for Mechanically

Assisted Circulatory Support

LVAD = left ventricular assist

device

NYHA = New York Heart

Association

J A C C : H E A R T F A I L U R E V O L . 6 , N O . 9 , 2 0 1 8 Hernandez et al.S E P T E M B E R 2 0 1 8 : 7 3 4 – 4 2 Rescue CRT in Inotrope-Dependent Heart Failure Patients

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D espite multiple advances in the field ofheart failure (HF), the mortality rate of pa-tients with advanced disease continues to

be exceptionally high (1,2). Among these patients,those with end-stage HF requiring inotropic supportlikely have the worse prognosis with medical man-agement (3,4).

Heart transplantation remains the gold standardtherapy 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 thosepatients waiting for transplant, as destination ther-apy and, in a smaller group, as a bridge to recovery(5). LVAD technology offers survival benefit andimproved quality of life when compared with medicaltherapy alone (6–8), but it does come at the risk ofwell-described complications, financial cost, andsome contraindications (9–14).

Along with this, significant numbers of trials havedemonstrated the beneficial effect of cardiacresynchronization therapy (CRT) in the treatment ofpatients with HF by reducing morbidity and mortalityin those patients with systolic dysfunction, prolongedQRS complex duration, and New York Heart Associa-tion (NYHA) functional class III or IV symptoms, whencombined with optimal pharmacotherapy (15). How-ever, during initial trials, NYHA functional class IVpatients not only were underrepresented but alsowere considered not to be CRT candidates because oftheir poor estimated survival (16). Hence, it iscurrently undetermined whether CRT may benefitthese patients. On the basis of a review of publishedreports, we sought to identify the possible benefits ofthis therapy in end-stage inotrope-dependentpatients.

METHODS

We undertook this systematic review according torecommendations of the Cochrane Collaboration andin line with the Preferred Reporting Items for Sys-tematic Reviews and Meta-Analysis (PRISMA) state-ment (17).

SEARCH STRATEGY FOR IDENTIFICATION OF

RELEVANT STUDIES. We systematically searchedMedline, Embase, Scopus, and the Cochrane Librarythrough March 2017 for full papers that evaluatedoutcomes after CRT in inotrope-dependent patientswithHF. No language limits were used. Databasesweresearched with the following terms: “end-stage heartfailure,” “catecholamine-dependent overt heart fail-ure,” “inotrope-dependent heart failure,” “advanced

heart failure,” “New York Heart Associationclass IV,” “NYHA class IV.” These terms weresearched individually with “cardiac resynch-ronization therapy” OR “CRT” OR “biven-tricular device,” combined by the booleanterm “AND.” This strategy was used both asMedical Subject Headings (MeSH) terms ifavailable and as free text. Reference lists fromall included studies were manually searchedfor additional studies.

SELECTION CRITERIA AND DATA EXTRACTION. Tobe eligible, studies were required to meet thefollowing inclusion criteria: 1) patients had to

be dependent on inotropic support at the time of CRTimplantation; 2) if the study included other patients,outcomes had to be specifically reported on theinotrope-dependent patients; 3) patients includedhad to be more than 18 years of age; and 4) papersincluded had to state a clear definition of “inotrope-dependence” or “inability to wean.” In most of theincluded studies, inotrope dependence was definedas the inability to wean or withdraw inotropic supportwithout noting clinical or biochemical parameterssuggestive of low cardiac output. Alternatively, insome studies, “inotrope-dependence” was endorsedby the treating cardiologist who considered thatinotropic therapy could not be safely withdrawn.Both definitions were acceptable for inclusion in ouranalysis. If the paper did not include a specific defi-nition, the corresponding authors were contacted tofurther query the selection criteria used. We excludedstudies containing patients with advanced HF thatwere not clearly dependent on inotropic support, andif the outcomes were not evidently distinguished inthe inotrope-dependent population.

Three investigators independently reviewed thestudy titles, abstracts, and full-length articles todetermine study inclusion and exclusion. These re-viewers also independently abstracted the studydesign, patients’ baseline characteristics, and relevantoutcomes. An electronic data formwas used to compileabstracted information. Differences were adjudicatedby consensus and by the senior author, whennecessary.

DATA ANALYSIS. A random-effects meta-analysiswas performed using pooled proportions, and het-erogeneity was examined using I2 statistics to deter-mine the overall mortality rate of patients oninotropic support after CRT implantation. In second-ary analysis, specific outcomes associated with CRTwere studied in a similar manner. Outcomes of in-terest included proportion of patients off inotropic

FIGURE 1 PRISMA Flow Diagram of Study Selection

PRISMA ¼ Preferred Reporting Items for Systematic Reviews and Meta-Analysis.

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support and proportion of patients who improvedtheir NYHA functional class after CRT. When avail-able, we analyzed survival estimates at 1 year, inwhich possible endpoints were all-cause mortality,LVAD implantation, or heart transplantation. AKaplan-Meier curve was generated to describe overallsurvival and survival free of LVAD. For the statisticalanalyses, we used Stata software version 13 (Stata-Corp., College Station, Texas).

RESULTS

STUDY SEARCH AND GENERAL CHARACTERISTICS. Thesearch retrieved 2,358 citations. Of these, 1,652 were

duplicates, and 654 were not related to the studyquestion on the basis of title and abstract review. Atotal of 52 studies were fully screened and assessedfor potential inclusion. Of these 52 studies, 8 fulfilledall criteria for inclusion (Figure 1) (18–25). All includedmanuscripts were retrospective observational ana-lyses. Details of the included studies and baselinecharacteristics of the study patients are listed inTable 1.

Overall, 151 patients were systematically reviewedand included for analysis. These patients were fol-lowed for 877 � 620 days and were mostly male(80%), with a mean age of 64 years. The patientsincluded were more likely to have ischemic

TABLE 1 Baseline Characteristics of Included Studies

First Author (Ref. #) NFollow-Up,

days Age, yrs Male

HF Etiology NYHAFunctionalClass IV

QRSDuration, ms

QRSConfiguration LVEF, % CRT-DICM NICM

Milliez et al. (18) 20 547 � 365 67 � 10 18 (90) 12 (60) 8 (40) 20 (100) 174 � 25 — 18 � 3 —

Cowburn et al. (19) 10 361 � 221 71 � 7 10 (100) 8 (80) 2 (20) 10 (100) 205 � 21 — 20 � 8 —

Herweg et al. (20) 10 1,088 � 284 55 � 13 9 (90) 4 (40) 6 (60) 10 (100) 153 � 25 LBBB: 7 (70)IVCD: 3 (30)

23 � 4 10 (100)

Hara et al. (21) 14 — 58 � 14 11 (79) 3 (21) 11 (79) 14 (100) 159 � 48 LBBB: 3 (21)RBBB: 1 (7)IVCD: 2 (14)Paced: 5 (36)None: 3 (21)

20.9 � 6.3 13 (93)

Sokal et al. (22) 11 1,163 � 538 63.7 � 12.6 9 (82) 8 (72) 3 (28) 11 (100) 190 � 34 LBBB: 6 (55) 19 � 4 11 (100)

Konstantino et al. (23) 10 — 68.6 � 5.0 9 (90) 10 (100) 0 10 (100) 170 � 17 LBBB: 8 (80)Paced: 2 (20)

— 8 (80)

Nakajima et al.(24) 26 1,033 � 742 55 � 18 19 (73) 19 (73) 7 (27) 26 (100) 159 � 38 LBBB: 11 (42)RBBB: 5 (19)IVCD: 10 (38)

23 � 7 —

Bhattacharya et al. (25) 50 927 � 730 68.3 � 9.2 36 (72) 32 (64) 18 (36) 20 (40) 172 � 34 RBBR: 6Non-RBBB: 44

20.3 � 7.4 50 (100)

Total 151 877 � 620 64 � 12 121 (80) 96 (64) 55 (36) 121 (80.1) 171 � 33 LBBB: 35 (50.2)RBBB: 6 (8.5)IVCD: 15 (21.1)Paced: 7 (9.9)

20.6 � 6.3 92 (96.8)

Values are n, mean � SD, or n (%).

CRT-D ¼ cardiac resynchronization therapy with defibrillator; HF ¼ heart failure; LBBB ¼ left bundle branch block; ICM ¼ ischemic cardiomyopathy; IVCD ¼ intraventricular conduction delay; LVEF ¼ leftventricular ejection fraction; NICM ¼ nonischemic cardiomyopathy; NYHA ¼ New York Heart Association; RBBB ¼ right bundle branch block.

J A C C : H E A R T F A I L U R E V O L . 6 , N O . 9 , 2 0 1 8 Hernandez et al.S E P T E M B E R 2 0 1 8 : 7 3 4 – 4 2 Rescue CRT in Inotrope-Dependent Heart Failure Patients

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cardiomyopathy (64%) than nonischemic cardiomy-opathy (36%) as the etiology of HF. Most patientswere in NYHA functional class IV (80.1%), and all hada left ventricular ejection fraction <30% and a sig-nificant intraventricular conduction delay on theirsurface electrocardiogram (QRS complex duration>130 ms). Although all of the studies reported theQRS complex duration, only 5 of 8 studies reportedthe QRS complex configuration. The most commonconfiguration was left bundle branch block (n ¼ 35)followed by intraventricular conduction delay (n ¼15), paced rhythm (n ¼ 9), and right bundle branchblock (n ¼ 6). When reported, most patients hadreceived CRT with a defibrillator (96.8%; n ¼ 95).

OUTCOMES. Seven of the 8 included studies reportedtheir inotrope weaning success. Our pooled analysisof those studies demonstrated that 93% of the re-ported patients were weaned from inotropic supportafter CRT implantation (95% confidence interval [CI]:86% to 100%). The overall heterogeneity, examinedthrough I2 statistics, of the proportion of patientsremaining off inotropic support was low, estimated at36.86% (Figure 2).

Six studies reported the NYHA functional classchange after CRT. In this regard, 2% improved toNYHA functional class I (95% CI: 2% to 6%), 36% ofthese patients improved to NYHA functional class II

(95% CI: 15% to 57%), 43% improved to NYHA func-tional class III (95% CI: 10% to 76%), and only 10%remained in NYHA functional class IV (95% CI: 3% to18%) (Figures 3A to 3C). Nakajima et al. (24) reported 3deaths within the first 3 months and 3 patients whocould not be withdrawn from inotropic support; thesepatients have not been included in Figures 3A to 3C.All of the included studies reported 12-month survivalwith an overall survival rate of 69% (95% CI: 56% to83%) (Figure 4). Furthermore, during the first year offollow-up, 6 patients had undergone heart trans-plantation (included in the year-survival), and 53patients either had died or had undergone LVADimplantation and were included in the year-mortality; these patients were included in the sur-vival free of LVAD Kaplan-Meier curve. None of the 6patients who underwent heart transplantation duringthe first year were bridged with an LVAD.

Additionally, 6 studies reported periproceduralcomplications, which are summarized in OnlineTable 1. No fatal events were reported, and a total of9 nonfatal events (7.82%) were captured out of 115patients, most commonly device infection (1confirmed infection and 2 possible infections) andcontrast-induced nephropathy.

Funnel plots were constructed to assess publica-tion bias for key study outcomes (Online Figures 1A

FIGURE 2 Proportion of Patients Off Inotropic Support After CRT

CI ¼ confidence interval; CRT ¼ cardiac resynchronization therapy; ES ¼ effect size.

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and 1B). Egger’s test was used to assess for publica-tion bias because conventional funnel plots havebeen shown to be inaccurate for meta-analyses ofproportion studies (26). We found no significantpublication bias as estimated by Egger’s test for theproportion of patients weaned from inotropic support(p ¼ 0.06) and overall survival at 12 months (p¼ 0.20);however, this assessment may be limited by the smallnumber of studies included in the analysis.

DISCUSSION

Our analysis suggests that resynchronization therapymay enable inotrope-dependent patients to beweanedfrom inotropic support after CRT implantation andachieve significant improvement in symptoms andoverall survival.

The role of CRT in NYHA functional class IV pa-tients remained uncertain until Lindenfeld et al.(27) examined the outcomes of NYHA functionalclass IV ambulatory patients (non–inotrope depen-dent) enrolled in the COMPANION (Comparison ofMedical Therapy, Pacing, and Defibrillation in HeartFailure) trial to assess the potential benefits of CRTand CRT with a defibrillator. Their analysis sug-gested that CRT and CRT with a defibrillatorsignificantly improved time to all-cause mortalityand hospitalizations in NYHA functional class IVpatients, with a trend for improved mortality (27).Later, Herweg and Barold (28) commented on

published reports that included NYHA functionalclass IV patients who were receiving intravenousinotropic therapy at the time of CRT implantation.Their analysis proposed that CRT could providesurvival benefit in even the sickest end-stage pa-tients and suggested that CRT should not be auto-matically dismissed as contraindicated in patientswith NYHA functional class IV HF who are receivinginotropic support (28).

Heart transplantation remains the treatment ofchoice in patients with advanced refractory HF.Nevertheless, many patients are ineligible for car-diac transplantation because of advanced age,burden of comorbidities, or limited donor organsupply (5). Additionally, patients with poor socialsupport do not qualify for LVAD placement in mostcenters. The impending high costs related to LVADimplantation also limit the widespread use of thistherapy. For example, 3 of the 8 included studies(18,22,29) enrolled only patients (total of 45 pa-tients) described as being ineligible for hearttransplantation or LVAD (age and comorbiditiesbeing the most common contraindications), and ofthose, 60% (n ¼ 27) survived at 1 year. Theseselected patients who are not candidates for heartreplacement therapies could still benefit fromrescue CRT, rather than remaining on inotropes asdestination therapy.

Given the lack of randomized trials, comparingthese patients with a control group can be

FIGURE 3 NYHA Functional Class After CRT

Proportion of patients who improved to (A) New York Heart Association (NYHA) functional class II and (B) functional class III. (C) Proportion of patients who remained in

New York Heart Association functional class IV after cardiac resynchronization therapy (CRT). Abbreviations as in Figure 2.

FIGURE 4 Survival at 12 Months After CRT

CRT ¼ cardiac resynchronization therapy; other abbreviations as in Figure 2.

J A C C : H E A R T F A I L U R E V O L . 6 , N O . 9 , 2 0 1 8 Hernandez et al.S E P T E M B E R 2 0 1 8 : 7 3 4 – 4 2 Rescue CRT in Inotrope-Dependent Heart Failure Patients

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challenging; therefore, some studies have comparedthis these patients with the medical arm of theREMATCH (Randomized Evaluation of MechanicalAssistance for the Treatment of Congestive HeartFailure) study, given that these patients had similarbaseline characteristics with regard to diseaseseverity (19). At a 1-year follow-up, there was a 75%mortality rate in the medical treatment group of theREMATCH study (6). In our study, following CRTimplantation, there was an overall mortality rate of31% at 1 year. Thus, there may be a substantial mor-tality reduction when rescue CRT is used in inotrope-dependent patients with HF when compared withmedical treatment alone. When comparing our studypatients with the medical arm of the REMATCHstudy, mortality at 1 year was reduced from 75% to31%. Furthermore, our cohort had better outcomesthan the LVAD arm when our Kaplan-Meier curveswere superimposed (Figure 5A). However, it is worthnoting that REMATCH used a first-generation pulsa-tile LVAD on patients who were transplant ineligible,

FIGURE 5 The 1-Year Rate of Survival Free of LVAD in Rescue CRT Compared With

Landmark Trials

(A) Survival in REMATCH (Randomized Evaluation of Mechanical Assistance for the

Treatment of Congestive Heart Failure) versus survival with rescue cardiac resynchro-

nization therapy (CRT). (B) Event-free survival in ENDURANCE (The HeartWare Ventric-

ular Assist System as Destination Therapy of Advanced Heart Failure: the ENDURANCE

Trial) versus survival with rescue cardiac resynchronization therapy. (C) Event-free

survival in ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventric-

ular Assist Device and Medical Management) versus survival with rescue cardiac

resynchronization therapy. LVAD ¼ left ventricular assist device; OMM ¼ optimal

medical management. (A) Adapted with permission of the Massachusetts Medical So-

ciety from Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a left ventricular

assist device for end-stage heart failure. N Engl J Med 2001;345:1435–43. (B) Adapted

with permission of the Massachusetts Medical Society from Rogers JG, Pagani FD,

Tatooles AJ, et al. intrapericardial left ventricular assist device for advanced heart

failure. N Engl J Med 2017;376:451–60. (C) Adapted with permission of Elsevier from

Estep et al. (7).

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thus implying a sicker group of patients than ours(two-thirds of them receiving inotropic support).Nonetheless, when comparing only the 3 studies thatincluded transplant-ineligible patients, the survivalrate in the rescue CRT group remained higher (60%vs. 52%).

Although our results are promising, the 1-yearsurvival rate for patients with continuous-flowLVADs is higher than for those inotrope-dependentpatients who undergo CRT implantation (7,30).However, the rates of complications related toLVADs are higher than the rates of complicationswith CRT. In REMATCH, within 3 months of im-plantation, the probability of LVAD infection was28%. Within 6 months, the frequency of bleedingwas 42%, and the probability of device failure was35% at 24 months (6). In the ROADMAP (RiskAssessment and Comparative Effectiveness of LeftVentricular Assist Device and Medical Managementin Ambulatory Heart Failure Patient) study (7), sur-gical and nonsurgical bleeding accounted for 65% ofLVAD events. The composite adverse event rate forbleeding, driveline infection, pump thrombosis,stroke, ventricular arrhythmias, and worsening HFwas 1.89 events per patient-year in the LVAD groupversus 0.83 in the medical therapy group. Addi-tionally, more LVAD-treated patients (80%) than thecontrol group (62%) had rehospitalizations within 1year of enrollment. According to the 7th INTERMACS(Interagency Registry for Mechanically Assisted Cir-culatory Support) annual report, from 2012 to 2014,there were 4,420 bleeding events (per 100 patient-months), followed by 4,132 infections and 916strokes in the first 12 months after implantation of acontinuous-flow LVAD (5). In the recent multicenterMOMENTUM 3 (MagLev Technology in Patients Un-dergoing Mechanical Circulatory Support Therapywith HeartMate 3) study, a newer generation ofcontinuous-flow magnetically levitated centrifugal-flow pumps (HeartMate 3) showed improvement inclinical outcomes at 6 months resulting fromreduction in the rate of reoperation for pump mal-function; however, researchers found no significantbetween-group differences in the rates of death or inother adverse outcomes such as disabling stroke (31).By contrast, the safety of CRT has been evaluated ina meta-analysis of 9,677 patients with CRT or CRTwith a defibrillator and showed similar safety out-comes in both devices (15). In CRT alone, the implantsuccess 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 CRTalone, devices malfunctioned in 5% of patients, and

PERSPECTIVES

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 thera-

peutic 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.

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1.8% of patients required hospitalization for in-fections in the implant site.

Comparing our Kaplan-Meier survival curve withENDURANCE (The HeartWare Ventricular AssistSystem as Destination Therapy of Advanced HeartFailure: the ENDURANCE Trial) (30), a recentdestination therapy trial comparing axial with cen-trifugal continuous-flow devices, is also noteworthy;most of these patients had an INTERMACS profile of1 to 3 (>70%), and although there was no medicalarm of the trial, the year survival free of disablingstroke or pump replacement for either type of pumpwas roughly 71%, which is close to our 1-year sur-vival free of LVAD (Figure 5B). Finally, to be able tocompare our cohort’s outcomes with a more stablestudy group, we compared with to the ROADMAPstudy (7), which included patients in NYHA func-tional class III or IV who were not dependent onintravenous inotropic support. This trial showedthat 1-year survival with improved functional statuswas higher in patients with continuous-flow LVADswhen compared with optimal medical therapyincluding CRT (80% vs. 63%), with the benefitextending now to 2 years (32). Interestingly, whenoverlapping our survival curve (Figure 5C), it re-sembles that of the medical therapy group. Thiscomparison favors our discussion in that rescue CRTin inotrope-dependent patients improves hemody-namic parameters to resemble those of INTERMACS>4 and may even translate into better post-opera-tive results if rescue CRT is attempted before LVADimplantation.

Ultimately, these strategies may need to be directlycompared in a clinical trial. At present, there are norandomized trials evaluating the benefit of CRT inpatients who require inotropic support. Furthermore,scientific guidelines have not specifically addressedthe role of CRT in these patients (33).

STUDY LIMITATIONS. Our analysis has limitations,most of them inherent to the study design, retro-spective nature of the included studies, and lack ofcontrol group. Most of the articles assessed for eligi-bility reported positive outcomes, thus raising thepossibility of publication bias. Notwithstanding, wefound no significant publication bias as estimated byEgger’s test for the proportion of patients weaned offinotropic support and overall survival at 12 months.Additionally, nonuniform and unspecified enrollmentcriteria may confound the precise delineation andidentification of true responders. For example, 64%of the reported patients in our study had ischemiccardiomyopathy, and additional clinical parameters

such as scar burden and areas of delayed activationwere lacking.

Furthermore, the duration of HF and exposure toideal medical therapy are crucial because it is possiblethat patients who had a shorter duration of HF or whohad not been exposed to optimal medical therapy atthe time of CRT implantation may have higher chan-ces of response once guideline-directed therapies areinitiated.

CONCLUSIONS

The prognosis of inotrope-dependent patients withHF remains overwhelmingly poor in the absence ofheart replacement therapies. Our study suggests thatrescue CRT may be considered a viable therapeuticoption in inotrope-dependent patients with HF. Inthese patients, CRT could allow them to be weanedfrom inotropic therapy, improve their quality of life,and decrease the rate of mortality; furthermore, itmay serve as a possible bridge to heart trans-plantation or LVAD. Our results are encouraging andshould stimulate further research with larger, ran-domized, prospective studies to identify factors thatpredict a beneficial response to resynchronizationtherapy.

ADDRESS FOR CORRESPONDENCE: Dr. Gabriel A.Hernandez, Division of Advanced Heart Failure andTransplant Cardiology, Vanderbilt University MedicalCenter, 1215 21st Avenue South, Medical Center EastOffice 5037, Nashville, Tennessee 37232. E-mail:Antoniohgmd@gmail.com.

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KEY WORDS cardiac resynchronizationtherapy, heart failure, inotropes, New YorkHeart Association functional class IV

APPENDIX For a supplemental table andfigure, please see the online version of thispaper.