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J O U R N A L O F 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 V O L . 6 8 , N O . 1 4 , 2 0 1 6

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Cardiac Recovery During Long-TermLeft Ventricular Assist Device Support

Omar Wever-Pinzon, MD,a,b,c Stavros G. Drakos, MD, PHD,a,b,c Stephen H. McKellar, MD, MSC,a,c,d

Benjamin D. Horne, MPH, PHD,e William T. Caine, MD,a,e Abdallah G. Kfoury, MD,a,e Dean Y. Li, MD, PHD,a,b,c

James C. Fang, MD,a,b,c Josef Stehlik, MD, MPH,a,b,c Craig H. Selzman, MDa,c,d

ABSTRACT

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BACKGROUND The number of centers with left ventricular assist device (LVAD) research programs focused on

cardiac recovery is very small. Therefore, this phenomenon has been reported in real-world multi-center registries as a

rare event.

OBJECTIVES This study evaluated the incidence of cardiac recovery with an a priori LVAD implantation strategy of

bridge-to-recovery (BTR) and constructed a recovery predictive model.

METHODS The study included LVAD recipients registered in the Interagency Registry for Mechanically Assisted Circu-

latory Support (INTERMACS). Cardiac recovery was evaluated in BTR and non-BTR patients. A weighted score was derived

and externally validated in patients of the Utah Cardiac Recovery (UCAR) program.

RESULTS Of 15,138 INTERMACS patients, cardiac recovery occurred in 192 (1.3%). The incidence of recovery was 11.2%

(n ¼ 14) in BTR compared with 1.2% (n ¼ 178) in non-BTR patients (p < 0.0001). Independent predictors of recovery

included: age <50 years, non-ischemic cardiomyopathy, time from cardiac diagnosis <2 years, absence of ICD, creatinine

#1.2 mg/dl, and LVEDD <6.5 cm (c-index: 0.85; p < 0.0001). A weighted score termed I-CARS, effectively stratified

patients based on their probability of recovery. I-CARS was validated in the UCAR cohort (n ¼ 190) with good perfor-

mance (AUC: 0.94; 95% CI: 0.91 to 0.98). One-year survival after LVAD explantation, available in INTERMACS for 21

(11%) patients, was 86%.

CONCLUSIONS The incidence of cardiac recovery is higher in patients implanted with an a priori BTR strategy.

We developed a simple tool to help identify patients in whom recovery is feasible. In BTR patients with favorable

characteristics, I-CARS suggests a 24% probability of successful LVAD explantation. Large-scale studies to

better address post-explantation outcomes are warranted. (J Am Coll Cardiol 2016;68:1540–53)

© 2016 by the American College of Cardiology Foundation.

L eft ventricular assist devices (LVADs) are astandard therapeutic option for patients withadvanced heart failure (HF) refractory to med-

ical therapy (1,2), whether used for patients awaitingcardiac transplantation or as definitive therapy forthose ineligible for transplantation (3,4). Heart trans-plantation and chronic mechanical support withLVADs improve survival, symptoms, exercise toler-ance, and quality of life in this population (4–9).

m the aUtah Cardiac Recovery Program, Salt Lake City, Utah; bDivision o

lt Lake City, Utah; cVeterans Affairs Medical Center, Salt Lake City, Utah; dD

ool of Medicine, Salt Lake City, Utah; and the eIntermountain Medical Ce

pport from Abiomed Inc.; and has served as consultant for HeartWare. Dr.

dical; and Speakers Bureau fees from HeartWare. All other authors have

contents of this paper to disclose.

nuscript received April 27, 2016; revised manuscript received July 1, 2016

However, these treatment strategies are complexand associated with adverse effects (4,10–13) thatimpose a significant burden on patients and nega-tively affect resource utilization and overall publichealth (14–16).

Because the usual intent with an LVAD is eventualheart transplantation or lifetime support, researchefforts have been focused mainly on improving de-vice safety and performance. Consequently,

f Cardiology, University of Utah School of Medicine,

ivision of Cardiothoracic Surgery, University of Utah

nter, Murray, Utah. Dr. Drakos has received research

Stehlik has received research support from St. Jude

reported that they have no relationships relevant to

, accepted July 5, 2016.

AB BR E V I A T I O N S

AND ACRONYM S

ACE = angiotensin-converting

enzyme

ARB = angiotensin-receptor

blocker

AUC = area under the receiver-

operating characteristics curve

BTR = bridge-to-recovery

CI = confidence interval

HF = heart failure

I-CARS = INTERMACS Cardiac

Recovery Score

ICD = implantable

J A C C V O L . 6 8 , N O . 1 4 , 2 0 1 6 Wever-Pinzon et al.O C T O B E R 4 , 2 0 1 6 : 1 5 4 0 – 5 3 LVAD-Induced Cardiac Recovery

1541

clinicians and investigators have devoted less time tounderstanding what happens to the supported heart.Indeed, the mechanically unloaded heart can expe-rience reverse remodeling and significantly improvedmyocardial function, with the potential for cardiacrecovery and device explantation, thereby avoidingtransplantation or long-term mechanical circulatorysupport (17–21). Although retrospective studies sug-gest a low incidence of myocardial recovery (<1% to2%) (22,23), the lack of pre-specified protocols tomonitor and promote structural and functionalchanges that lead to cardiac recovery and LVADexplantation calls into question the accuracy of thesedata (24,25).

SEE PAGE 1554cardioverter-defibrillator

INTERMACS = Interagency

Registry for Mechanically

Assisted Circulatory Support

LVAD = left ventricular assist

device

LVEDD = left ventricular

end-diastolic dimension

LVEF = left ventricular

ejection fraction

R = Utah Cardiac Recovery

LVAD unloading of the failing heart is associatedwith unique genomic, molecular, cellular, and struc-tural changes that can be linked with functional heartimprovement (26–28). To date, few clinical and mo-lecular predictors of myocardial recovery have beenidentified (25,28). The objective of the current studywas to evaluate the incidence of cardiac recovery andpatient characteristics according to LVAD implanta-tion strategy (i.e., an a priori bridge-to-recovery[BTR] strategy vs. non-BTR strategy) in a largecohort of patients enrolled in a national registry. Inaddition, we aimed to construct and validate a pre-dictive model of cardiac recovery leading to LVADexplantation.

MATERIALS AND METHODS

The design, structure, and goals of the InteragencyRegistry for Mechanically Assisted Circulatory Sup-port (INTERMACS), a North American registry of pa-tients receiving mechanical circulatory supportdevice therapy, have been published elsewhere (29).Additional information can be found in the OnlineAppendix.

De-identified data of patients registered in INTER-MACS were provided to the authors. The study anal-ysis included adult (i.e., >18 years of age) LVADrecipients registered in INTERMACS between March2006 and June 2015. We excluded patients whoreceived a right ventricular assist device without anLVAD, a total artificial heart, or prior heart transplan-tation. Patients with limited follow-up (<30 days),complex congenital heart disease, and hypertrophicor other forms of restrictive cardiomyopathy wereexcluded from the competing-risk regression modelsbuilt to assess the association of patient-relatedfactors with cardiac recovery to eliminate a groupof patients with different potential for cardiac

recovery. The INTERMACS dataset did notprovide detailed information to identify andexclude from the regression model patientswith acute forms of HF (e.g., acute myocar-dial infarction, acute myocarditis). Use ofthese data was deemed exempt from humansubject approval by our institutional reviewboards.

VALIDATION COHORT. The Utah CardiacRecovery (UCAR) program has prospectivelyenrolled patients who required circulatorysupport with a continuous-flow LVAD (25).The program prospectively collects longitu-dinal clinical, hemodynamic, and cardiacimaging data before and after LVAD implan-tation to better define the structural andfunctional effects of mechanical unloading onthe failing myocardium. We included adultLVAD recipients enrolled from July 2008 toApril 2015 and again excluded patients withacute forms of HF, hypertrophic or infiltrativecardiomyopathies, and complex congenitalheart disease. Informed consent was ob-tained from all patients, and the institutional

review board of the participating institutionsapproved the study.

STATISTICAL ANALYSIS. Baseline characteristicswere summarized by using standard statistical de-scriptors and compared by using the Mann-WhitneyU test or Pearson chi-square test as appropriate.The primary outcome was the incidence of cardiac re-covery, defined as LVAD explantation due to myocar-dial recovery. Patients who experienced myocardialrecovery but had their pump deactivated and left insitu without device removal were also included in theprimary outcome. Other outcomes included mortalityon LVAD support, transplantation, and LVAD explan-tation due to nonrecovery reasons. Time to event wasthe time from LVAD implantation until cardiac recov-ery, death on LVAD support, transplantation, LVADexplantation due to nonrecovery reasons, or lastfollow-up in patients who remained on LVAD support.

Outcomes were evaluated in the entire derivationcohort and subgroups of patients on the basis of LVADimplantation strategy: BTR and non-BTR thatincluded bridge-to-transplant, bridge-to-candidacy,destination therapy, and rescue therapy. Survivalcurves were constructed to illustrate multiplepossible outcomes at any time after LVAD implanta-tion: cardiac recovery, death on LVAD support,transplantation, and LVAD explantation due to non-recovery reasons. Cumulative incidence functioncurves were estimated by means of the Fine and Gray

UCA

TABLE 1 Characteristics of LVAD Recipients

BTR(n ¼ 125)

BTT(n ¼ 4,284)

BTC(n ¼ 5,027)

DT(n ¼ 5,601)

Rescue/Other(n ¼ 101) p Value

Clinical data

Age group <0.0001

19–29 yrs 20.0 6.1 6.3 2.3 8.9 –

30–39 yrs 13.6 9.6 9.1 4.7 8.9 –

40–49 yrs 19.2 18.3 17.2 9.6 14.8 –

50–59 yrs 25.6 32.6 33.2 19.9 33.7 –

60–69 yrs 16.0 31.7 31.0 33.9 31.7 –

70–79 yrs 5.6 1.7 3.0 28.1 2.0 –

$80 yrs 0 0 0.2 1.4 0 –

Male 62.4 78.6 76.6 80.4 69.3 <0.0001

Ethnicity <0.0001

Non-Hispanic 95.1 92.4 93.4 94.1 86.7 –

Hispanic 4.9 7.1 6.4 5.3 10.0 –

Other 0 0.5 0.2 0.6 3.3 –

BMI, kg/m2 27.6 (24.1–32.9) 27.7 (24.1–31.4) 28.3 (24.4–33.0) 27.8 (24.0–32.6) 29.2 (24.6–34.0) 0.0001

HF etiology <0.0001

Nonischemic 62.4 58.4 52.8 42.6 40.6 –

Ischemic 33.6 37.8 43.9 54.7 56.4 –

Congenital 1.6 1.0 0.5 0.3 0 –

Restrictive 0.8 2.4 2.0 1.5 0 –

Time since cardiac diagnosis <0.0001

<1 month 38.4 4.1 10.2 4.0 38.6 –

1 month–1 yr 15.2 10.4 11.9 8.4 10.9 –

1–2 yrs 6.4 6.4 7.0 5.3 10.9 –

>2 yrs 36.8 76.1 66.4 78.1 29.7 –

Implanted ICD 31.2 84.1 72.6 82.7 23.8 <0.0001

Prior cardiac surgery 39.2 31.5 30.6 42.9 42.6 <0.0001

Chronic kidney disease 0 0.4 8.2 16.2 7.1 <0.0001

NYHA functional class IV 70.4 73.2 71.9 78.0 79.2 <0.0001

LVEF, % 10 (10–25) 10 (10–25) 10 (10–25) 10 (10–25) 10 (10–10) 0.0001

LVEDD, cm 5.9 (5.0–7.1) 6.9 (6.2–7.6) 6.8 (6.0–7.6) 6.7 (6.0–7.4) 6.2 (5.6–6.9) 0.0001

INTERMACS profile <0.0001

INTERMACS 1 57.4 16.3 22.8 13.4 80.0 –

INTERMACS 2 19.7 42.6 37.1 33.7 10.0 –

INTERMACS 3 15.6 26.8 24.1 32.7 7.0 –

INTERMACS 4 4.9 10.7 11.9 15.6 1.0 –

INTERMACS 5–7 2.4 3.6 4.1 4.6 2.0 –

Support at implantation

Mechanical ventilation 8.0 3.0 5.2 4.0 24.8 <0.0001

Dialysis 11.2 3.1 3.9 2.8 6.9 <0.0001

IABP 8.8 14.3 16.2 17.4 16.8 <0.0001

ECMO 0.8 0.8 0.7 0.9 7.9 <0.0001

Biochemical data

Sodium, mEq/l 137 (134–139) 135 (132–138) 135 (132–138) 136 (132–138) 137 (134–141) 0.0001

Creatinine, mg/dl 1.2 (0.9–1.5) 1.3 (1.0–1.6) 1.2 (1.0–1.6) 1.3 (1.0–1.7) 1.4 (1.0–1.9) 0.0001

Albumin, g/dl 3.0 (2.7–3.4) 3.5 (3.1–3.9) 3.3 (2.9–3.8) 3.4 (3.0–3.8) 2.9 (2.4–3.5) 0.0001

BNP, pg/ml 761 (466–1,682) 787 (393–1,526) 866 (439–1,580) 816 (405–1,573) 1,018 (285–1,718) 0.09

Continued on the next page

Wever-Pinzon et al. J A C C V O L . 6 8 , N O . 1 4 , 2 0 1 6

LVAD-Induced Cardiac Recovery O C T O B E R 4 , 2 0 1 6 : 1 5 4 0 – 5 3

1542

method and compared by using the Gray test (30,31).Univariable and multivariable proportional hazardsmodels were used to assess predictors for cardiac re-covery. The proportional hazards assumption wasconfirmed by testing covariate interactions withquadratic function of time and checked graphically by

using Schoenfeld-type residuals. The Fine and Graymethod was used to build the models and generatesubhazard ratios and 95% confidence intervals (CIs)to account for death on LVAD support, trans-plantation, or LVAD explantation due to nonrecoveryreasons as competing risk events for cardiac recovery.

TABLE 1 Continued

BTR(n ¼ 125)

BTT(n ¼ 4,284)

BTC(n ¼ 5,027)

DT(n ¼ 5,601)

Rescue/Other(n ¼ 101) p Value

MCS data

Device type <0.0001

LVAD 68.8 93.2 93.1 97.4 72.3 –

BiVAD 31.2 6.8 6.9 2.6 27.7 –

LVAD design <0.0001

Continuous-flow 48.8 90.6 90.8 96.7 63.4 –

Pulsatile-flow 51.2 9.4 9.2 3.3 36.6 –

Continuous-flow LVAD type <0.0001

Axial-flow 95.1 69.7 86.3 99.0 92.2 –

Centrifugal-flow 4.9 30.3 13.7 1.0 7.8 –

Center volume <0.0001

1–10 implants 5.7 7.1 10.2 10.6 12.1 –

11–20 implants 14.8 15.6 18.0 13.4 14.1 –

21–30 implants 32.8 23.0 19.4 17.9 28.3 –

31–50 implants 22.1 28.3 30.5 30.4 29.3 –

>50 implants 24.6 26.0 21.9 27.6 16.2 –

Values are % or median (interquartile range).

BiVAD ¼ biventricular assist device; BNP ¼ B-type natriuretic peptide; BMI ¼ body mass index; BTC ¼ bridge-to-candidacy; BTR ¼ bridge to recovery; BTT ¼ bridge-to-transplantation; DT ¼ destination therapy; ECMO ¼ extracorporeal membrane oxygenator; HF ¼ heart failure; IABP ¼ intra-aortic balloon pump; ICD ¼ implantablecardioverter-defibrillator; INTERMACS ¼ Interagency Registry for Mechanically Assisted Circulatory Support; LVAD ¼ left ventricular assist device; LVEDD ¼ left ventricularend-diastolic dimension; LVEF ¼ left ventricular ejection fraction; MCS ¼ mechanical circulatory support; NYHA ¼ New York Heart Association.

J A C C V O L . 6 8 , N O . 1 4 , 2 0 1 6 Wever-Pinzon et al.O C T O B E R 4 , 2 0 1 6 : 1 5 4 0 – 5 3 LVAD-Induced Cardiac Recovery

1543

The models examined the association of factors orcharacteristics present at time of LVAD implantationwith cardiac recovery. A multivariable competing-riskregression model was used to determine the inde-pendent association of multiple patient-relatedfactors on the 5-year hazard of cardiac recovery(follow-up was censored after 5 years). Variablespresumed to be potentially associated with cardiacrecovery based on literature review and clinicaljudgment, as well as those significant at the p < 0.10level in unadjusted analyses, were included in themultivariable analysis. Only variables significant atthe p < 0.05 level on the basis of the likelihood ratiotest were retained in the final model. A 2-tailedp value <0.05 was considered statistically signifi-cant. Patients from the UCAR program were excludedfrom the INTERMACS derivation cohort when build-ing the prognostic scoring model.

A practical prognostic scoring system was devel-oped (using methods described in the OnlineAppendix), and patients were divided into categoriesof low, intermediate, or high probability of cardiacrecovery. The predictive discrimination of the scoringsystem was examined by calculating the Harrell’sconcordance (C) statistic. The prognostic scoring sys-temwas externally validated in an independent cohortof patients from the UCAR program (validationcohort). Analyses were performed by using STATAversion 14 (StataCorp LP, College Station, Texas).

RESULTS

There were 15,631 adults enrolled between March2006 and June 2015. We excluded patients whoreceived a right ventricular assist device without anLVAD (n ¼ 111), a total artificial heart (n ¼ 355), or aprevious heart transplant (n ¼ 27). In total, 15,138patients met the inclusion criteria and comprised theINTERMACS cohort (Online Figure 1).

The distribution and characteristics of the LVADrecipients, stratified according to implantation strat-egy, are summarized in Table 1. Although between-group comparisons for most baseline characteristicswere statistically significant, several elements wereparticularly relevant. Patients who had an LVADimplanted with an a priori BTR strategy were morelikely to be young female subjects with lower bodymass index who more often had nonischemic car-diomyopathy and a shorter time since their cardiacdiagnosis. This group was less likely to have animplantable cardioverter-defibrillator (ICD) or chronickidney disease, and had lower left ventricularend-diastolic dimensions (LVEDDs). Finally, thesepatients had lower INTERMACS profiles (higheracuity), were more likely to require dialysis duringthe index admission or require a biventricular assistdevice and less likely to require an intra-aorticballoon pump; they also had lower levels of serumcreatinine and B-type natriuretic peptides.

FIGURE 1 Cardiac Recovery

0 12 24 36 48 60 72 84 96Time (Months)

.015

.01

.005

0Cum

ulat

ive

Inci

denc

e of

Car

diac

Rec

over

y

0 12 24 36 48 60 72 84 96Time (Months)

.15

.1

.05

0Cum

ulat

ive

Inci

denc

e of

Car

diac

Rec

over

y

BTR strategy

Non-BTR strategy

p<0.0001

A B

The cumulative incidence of cardiac recovery, defined as left ventricular assist device explantation, is shown for (A) the entire Interagency Registry for

Mechanically Assisted Circulatory Support cohort and (B) subgroups on the basis of a bridge-to-recovery (BTR) left ventricular assist device implantation

strategy.

Wever-Pinzon et al. J A C C V O L . 6 8 , N O . 1 4 , 2 0 1 6

LVAD-Induced Cardiac Recovery O C T O B E R 4 , 2 0 1 6 : 1 5 4 0 – 5 3

1544

Interestingly, they were more likely to receive apulsatile-flow LVAD; those receiving a continuous-flow device were more likely to receive an axial-flowLVAD.

After a median of 323.3 days (range 176.9 to 656.4days), 192 (1.3%) of the total INTERMACS patientpopulation experienced cardiac recovery leading toLVAD explantation (n ¼ 172) or device deactivation(n ¼ 20). Nonrecovery reasons for device explantationincluded device malfunction (n ¼ 528), device infec-tion (n ¼ 116), and device thrombosis (n ¼ 620). A totalof 202 patients underwent device explantation ordeactivation for other reasons (likely for palliativepurposes). The hazard estimates and cumulativeincidence function of cardiac recovery in this cohortare shown in Online Figure 2 and Figure 1A, respec-tively. Cardiac recovery occurred infrequently earlyafter LVAD implantation. Among patients who expe-rienced cardiac recovery (n ¼ 192), only 4 (2.1%) did soin the first month, but recovery frequency increasedover time: 28 (14.6%) patients experienced cardiacrecovery by 3 months, with 80% of recoveries occur-ring by 2 years’ post-LVAD implantation (OnlineFigure 3).

There was no significant variation in the incidenceof cardiac recovery among centers with differentimplant volumes (Online Table 1). LVAD recipients inwhom cardiac recovery occurred had evidence ofreverse remodeling based on longitudinal improve-ment in left ventricular ejection fraction (LVEF) andreduction in LVEDD compared with patients with no

cardiac recovery (Online Figure 4). Of significance,there were 7,084 patients who had at least 1 follow-upechocardiogram with LVEF assessment after 3months of LVAD support. In this group, 892 (12.6%)patients achieved an LVEF $40%, with a relativeincrease in LVEF $50%. Of these patients who expe-rienced a favorable cardiac response, 97% underwentimplantation with the use of a non-BTR strategy.

The incidence of cardiac recovery varied widelydepending on the implantation strategy (Figure 1B).Cardiac recovery was observed in 14 (11.2%) patientswith an a priori strategy of BTR, corresponding to anincidence rate of 7.3 events per 100 person-years,versus 178 (1.2%) patients with a non-BTR strategy,corresponding to an incidence rate of 0.9 event per100 person-years (p < 0.0001). Nonrecovery-relatedexplants were also more common in the BTRstrategy group compared with the non-BTRstrategy group (6.8 vs. 3.6 events per 100 person-years; p ¼ 0.04). Analysis of the different outcomesexperienced by LVAD recipients revealed varyingrates at 12 and 36 months after implantation (Table 2,Figures 2A to 2C).

To better characterize patients considered to havea good potential for cardiac recovery, we comparedthe characteristics of a priori BTR strategy patientswho experienced cardiac recovery versus those whodid not. Successfully explanted patients tended to beyounger, were more likely women of Hispanicethnicity, had lower body mass index and shorterduration of HF, were less likely to have an ICD or

TABLE 2 Cumulative Incidence

Overall BTR Strategy Non-BTR Strategy

12 Months 36 Months 12 Months 36 Months 12 Months 36 Months

Cardiac recovery 0.7 1.2 8.8 10.4 0.6 1.1

LVAD explantation(nonrecovery reasons)

0.7 2.6 0.8 3.2 0.6 2.6

Transplantation 19.6 28.3 20.0 27.2 19.5 28.0

Mortality on LVAD support 18.3 26.3 22.4 24.8 18.2 26.1

Ongoing LVAD support 60.7 41.6 48.0 34.4 61.0 42.1

Values are %.

Abbreviations as in Table 1.

J A C C V O L . 6 8 , N O . 1 4 , 2 0 1 6 Wever-Pinzon et al.O C T O B E R 4 , 2 0 1 6 : 1 5 4 0 – 5 3 LVAD-Induced Cardiac Recovery

1545

previous cardiac surgeries, and were more symp-tomatic (Online Table 2).

THE INTERMACS CARDIAC RECOVERY SCORE. Theassessment of the clinical characteristics of patientswho experienced cardiac recovery showed that, withfew exceptions, this group was fairly homogeneous,independent of the LVAD implantation strategy(BTR vs. non-BTR strategy) (Table 3). However, therewere marked differences in the baseline characteris-tics of patients with and without cardiac recovery. Weperformed a competing-risks regression analysis inthe INTERMACS cohort that excluded patients withfollow-up <30 days (n ¼ 186), complex congenital(n ¼ 81) and restrictive (n ¼ 289) heart disease, andpatients from the UCAR program (n ¼ 247). Follow-upwas censored at 5 years’ post-LVAD implantation.A total of 14,338 patients (185 cardiac recoveryevents) were analyzed.

Among the characteristics present at time of LVADimplantation that were included in our analyses,multiple univariable predictors of cardiac recoverywere identified (Online Table 3). Of significance,

FIGURE 2 Competing Outcomes Curves

Non-Recovery Explant Death

100

80

60

40

20

0

0 12 24 36 48 60 72 84 96Time (Months)

LVAD

Rec

ipie

nts (

%)

100

80

60

40

20

0

0 12 24

LVAD

Rec

ipie

nts (

%)

A

C

Competing outcomes curves show similar patterns for the (A) overall coh

(C) bridge-to-recovery strategy group. Outcome events are mutually ex

cardiac recovery did not occur in patients with com-plex congenital and restrictive heart disease. Aftermultivariable adjustment, 6 independent predictorsof cardiac recovery were identified: age <50 years,nonischemic cardiomyopathy, time from cardiacdiagnosis <2 years, absence of an ICD, serum creati-nine level #1.2 mg/dl, and LVEDD <6.5 cm (Table 4).The discrimination of the model for cardiac recoverywas good, with a C-statistic of 0.85 (95% CI: 0.82 to0.88; p < 0.0001).

Cardiac Recovery Ongoing Support Transplant

100

80

60

40

20

0

0 12 24 36 48 60 72 84 96Time (Months)

LVAD

Rec

ipie

nts (

%)

36 48 60 72 84 96Time (Months)

B

ort and (B) the non–bridge-to-recovery strategy group, with some variations in the

clusive. LVAD ¼ left ventricular assist device.

TABLE 3 Characteristics of LVAD Recipients Stratified According to Cardiac Recovery

Cardiac Recovery (Explanted)(n ¼ 192)

No Recovery(n ¼ 14,946)

p Value(Recovery vs. No Recovery)

BTR(n ¼ 14)

No BTR(n ¼ 178)

All Recovery(n ¼ 192)

Clinical data

Age group <0.0001

19–29 yrs 35.7 16.3 17.7 4.7 –

30–39 yrs 28.6 19.1 19.8 7.5 –

40–49 yrs 7.1 25.3 24.0 14.6 –

50–59 yrs 7.1 22.5 21.4 28.1 –

60–69 yrs 14.3 14.6 14.6 32.4 –

70–79 yrs 7.1 2.2 2.6 12.1 –

$80 yrs 0 0 0 0.6 –

Age, yrs 35 (24–55) 45 (35–55)* 45 (35–55) 55 (45–65) 0.0001

Male 35.7 61.2† 59.4 78.7 <0.0001

Ethnicity ‡ 0.64

Non-Hispanic 71.4 95.5 93.8 93.3 –

Hispanic 28.6 4.5 6.2 6.2 –

BMI, kg/m2 25.7 (20.5–30.0) 26.6 (23.4–30.9)* 26.6 (23.0–30.8) 28.0 (24.2–32.4) 0.005

Blood type O 35.7 52.8* 51.6 47.2 0.22

HF etiology * <0.0001

Nonischemic 92.9 83.7 84.4 50.2 –

Ischemic 7.1 14.6 14.1 46.6 –

Congenital 0 1.7 0 0.5 –

Restrictive 0 0 0 1.9 –

Time since cardiac diagnosis ‡ <0.0001

<1 month 78.6 28.1 31.8 6.3 –

1 month–1 yr 7.1 23.6 22.4 10.0 –

1–2 yrs 0 9.6 8.9 6.2 –

>2 yrs 14.3 32.6 31.2 73.6 –

Implanted ICD 7.1 41.0§ 38.5 79.4 <0.0001

Previous cardiac surgery 14.3 16.8* 16.7 35.8 <0.0001

NYHA functional class ‡ <0.0001

III 0 12.9 12.0 17.0

IV 78.6 70.8 71.4 74.6

LVEF, % 10 (10–25) 10 (10–10)* 10 (10–25) 10 (10–25) 0.24

LVEDD, cm 5.4 (4.5–6.3) 6.4 (5.7–7.0)‡ 6.3 (5.6–7.0) 6.8 (6.1–7.5) 0.0001

INTERMACS profile † <0.0001

INTERMACS 1 71.4 27.7 30.9 18.0 –

INTERMACS 2 7.1 28.2 26.7 37.2 –

INTERMACS 3 21.4 32.2 31.4 27.8 –

INTERMACS 4 0 6.8 6.3 12.9 –

INTERMACS 5–7 0 5.1 4.7 4.1 –

Support at implantation

Mechanical ventilation 7.1 7.9* 7.8 4.2 0.01

Dialysis 0 3.9* 3.6 3.3 0.81

IABP 7.1 10.7* 10.4 16.1 0.03

ECMO 0 1.7* 1.6 0.9 0.29

Biochemical data

Sodium, mEq/l 136 (134–137) 136 (133–139)* 136 (133–139) 135 (132–138) 0.047

Creatinine, mg/dl 1.0 (0.8–1.4) 1.1 (0.8–1.3)* 1.1 (0.8–1.3) 1.3 (1.0–1.7) 0.0001

Albumin, g/dl 3.0 (2.4–3.3) 3.4 (2.8–3.7)† 3.3 (2.8–3.7) 3.4 (3.0–3.8) 0.009

BNP, pg/ml 972 (745–1,070) 707 (346–1,121)* 742 (377–1,090) 825 (412–1,565) 0.10

Continued on the next page

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On the basis of these results, a prognostic score welabeled the INTERMACS Cardiac Recovery Score(I-CARS) was derived by assigning each of the 6prognostic variables a number of points proportional

to its regression coefficient (Table 4). A score wasdetermined for each patient by calculating a sum ofthe points corresponding to his or her risk factors.The score ranged from 0 to 9, and the median was 3

TABLE 3 Continued

Cardiac Recovery (Explanted)(n ¼ 192)

No Recovery(n ¼ 14,946)

p Value(Recovery vs. No Recovery)

BTR(n ¼ 14)

No BTR(n ¼ 178)

All Recovery(n ¼ 192)

MCS data

Device type ‡ 0.79

LVAD 57.1 97.8 94.8 94.4 –

BiVAD 42.9 2.2 5.2 5.6 –

LVAD design ‡ <0.0001

Continuous-flow 35.7 88.8 84.9 92.5 –

Pulsatile-flow 64.3 11.2 15.1 7.5 –

Continuous-flow LVAD type * 0.001

Axial-flow 100 95.6 95.7 86.6

Centrifugal-flow 0 4.4 4.3 13.4

Center volume * 0.40

1–10 implants 7.1 7.3 7.3 9.5 –

11–20 implants 21.4 19.1 19.3 15.5 –

21–30 implants 35.7 15.2 16.7 20.1 –

31–50 implants 21.4 32.6 31.8 29.8 –

>50 implants 14.3 25.8 25.0 25.1 –

Values are % or median (interquartile range). *p $ 0.1. †0.05 # p < 0.1. ‡p < 0.01. §0.01 # p < 0.05.

Abbreviations as in Table 1.

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(interquartile range: 1 to 5). Cardiac recovery esti-mates were used to define 3 groups with significantlydifferent prognoses: a low probability group (0 to 3points), an intermediate probability group (4 to 6),and a high probability group (7 to 9). The corre-sponding cardiac recovery rates in the INTERMACScohort were 0.2%, 1.4%, and 8.9% (Figure 3A). Inter-estingly, applying I-CARS to the BTR strategy groupyielded cardiac recovery rates of 0%, 4.9%, and 24.5%for patients in the low, intermediate, and high prob-ability categories, respectively. Cardiac recovery ratesstratified according to I-CARS in the non-BTR strategygroup were similar to rates in the main cohort. Theperformance of I-CARS was good, with an area underthe receiver-operating characteristics curve (AUC) of

TABLE 4 Multivariable Predictors of Cardiac Recovery and Prognosti

No. of Patients(N ¼ 14,338)

No. of PatientsWith CR(N ¼ 185)

P(Eve

Age <50 yrs (vs. $50 yrs) 3,848 (26.8) 112 (60.5)

Nonischemic CM (vs. ischemic CM) 7,427 (51.8) 155 (83.8)

Time from cardiac diagnosis <2 yrs(vs. $2 yrs)

3,310 (23.1) 114 (61.6)

Implanted ICD (no vs. yes) 3,004 (21.0) 113 (61.1)

Creatinine #1.2 mg/dl (vs. >1.2 mg/dl) 6,702 (46.7) 132 (71.4)

LVEDD <6.5 cm (vs. $6.5 cm) 4,084 (28.5) 82 (44.3)

Values are n (%) unless otherwise indicated. The model was built using competing-risks

CI ¼ confidence interval; CM ¼ cardiomyopathy; CR ¼ cardiac recovery; SHR ¼ subha

0.84 (95% CI: 0.81 to 0.87) (Figure 3B). The scoredistribution of I-CARS stratified according toimplantation strategy and the presence of cardiacrecovery are shown in Online Figures 5 and 6,respectively.

Cardiac recovery occurred infrequently early afterLVAD implantation and increased in frequency overtime (Online Figure 3). Thus, including patients whodid not have the opportunity to disclose their car-diac recovery potential could affect our results.To address this question, we excluded patientswho died (n ¼ 1,396) or underwent transplantation(n ¼ 609) within the first 3 months’ post-LVADimplantation. Interestingly, 5 patients with an apriori BTR implantation strategy underwent

c Score System

Incidence Rate of CRby Prognostic Factorresent Versus Absentnt per 100 Person-Years) SHR (95% CI) p Value

b RegressionCoefficient Score

2.2 vs. 0.5 1.91 (1.36–2.68) <0.0001 0.65 1

1.6 vs. 0.3 4.67 (3.06–7.14) <0.0001 1.54 3

2.7 vs. 0.5 2.18 (1.52–3.14) <0.0001 0.78 1

2.9 vs. 0.5 3.68 (2.59–5.23) <0.0001 1.30 2

1.4 vs. 0.5 1.97 (1.42–2.73) <0.0001 0.68 1

1.6 vs. 0.7 1.81 (1.33–2.46) <0.0001 0.59 1

regression by the Fine and Gray method.

zard ratio; other abbreviations as in Table 1.

FIGURE 3 I-CARS: Derivation Cohort

25

20

15

10

5

0

Card

iac

Reco

very

(%)

Overall Non-BTR BTRLow probabilityIntermediate probabilityHigh probability

(0-3)(4-6)(7-9)

0.21.48.9

0.21.38.1

0.04.824.5

1.00

0.75

0.50

0.25

0.00

0.00 0.25 0.50 0.75 1.001 - Specificity

Sens

itivi

ty

Area under ROC curve = 0.8429

A B

(A) The INTERMACS Cardiac Recovery Score (I-CARS) effectively stratified patients on the basis of the probability of cardiac recovery. (B) The area under the

receiver-operating characteristics curve (ROC) demonstrated good discrimination of I-CARS for cardiac recovery. BTR ¼ bridge-to-recovery.

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transplantation and another 10 patients in this groupdied within the first 3 months after implantation.Cardiac recovery rates conditional to survival on anLVAD 3 months after implantation were 1.5% in theentire cohort, 1.4% with the non-BTR strategy, and13.1% in the BTR strategy group. Univariable andmultivariable predictors of cardiac recovery condi-tional to 3-month survival after LVAD implantationdid not differ significantly from the original analysis(data not shown).

HF HISTORY AND CARDIAC RECOVERY. The poten-tial for cardiac recovery is greater in patients withacute forms of HF (e.g., acute myocarditis or after anacute myocardial infarction); including these patientsmay therefore result in an overestimation of cardiacrecovery and could affect the predictors associatedwith this outcome. To address this issue, patients whohadHF for<1month andwho had normal LVEDD (#5.8cm in men and #5.2 cm in women) were excluded (32).A total of 228 patients were excluded, including 15LVAD recipients who experienced cardiac recovery.The cardiac recovery rate in this cohort was 1.5%, andpredictors of cardiac recovery did not differ signifi-cantly from the original analysis (Online Table 4).

The use of antiremodeling agents was common inLVAD patients (Online Table 5). Patients who expe-rienced cardiac recovery were less frequently taking abeta-blocker, angiotensin-converting enzyme (ACE)inhibitor/angiotensin-receptor blocker (ARB), oraldosterone receptor antagonist before LVAD im-plantation. After LVAD implantation, compared with

those with no recovery, patients with cardiac recov-ery were more frequently taking a beta-blocker(12 months: 95% vs. 77%; p < 0.01), an ACE inhibitoror ARB (12 months: 80% vs. 53%; p < 0.01), or analdosterone receptor blocker (12 months: 49% vs.34%; p ¼ 0.05). The use of beta-blockers, ACEinhibitors or ARBs, and mineralocorticoid receptorantagonists was associated with cardiac recovery onunivariable analysis (Online Table 3). Patients withcardiac recovery were less likely to be taking adiuretic compared with patients without recovery.

VALIDATION COHORT. Within the UCAR program,206 patients underwent LVAD implantation duringthe study period. We prospectively excluded subjectswith acute forms of HF (n ¼ 13) and hypertrophic orinfiltrative cardiomyopathies (n ¼ 3). The remaining190 subjects with chronic advanced cardiomyopathyformed the UCAR validation cohort. Baseline charac-teristics (Online Table 6) had a median age of 60 years(range 48 to 68 years), 83% were men, 71% were inNew York Heart Association functional class IV, me-dian duration of symptoms was 5 years, and medianLVEDD was 6.7 cm (range 6.2 to 7.3 cm). Nearly two-thirds of the patients were inotrope dependent andof higher acuity according to their INTERMACS pro-file. Nonischemic cardiomyopathy was the mostfrequent etiology (56%).

In the validation cohort, the prognostic value ofI-CARS was investigated in 2 populations: first,patients who had an improvement in LVEF $50%relative to baseline and a final LVEF $40%

FIGURE 4 I-CARS: Validation Cohort

Patie

nts (

%)

Cardiac Response Cardiac Recovery

A

50

40

30

20

7.4

0.0

15.6

6.3

50.0

38.9

10

0

Sens

itivi

ty

B

1.00

0.00

Low probabilityLow probability High probabilityIntermediate probability

0.25

0.50

0.75

1.000.00 0.25 0.50 0.751 - Specificity

Sens

itivi

ty

C

1.00

0.00

0.25

0.50

0.75

1.000.00 0.25 0.50 0.751 - Specificity

AUC: 0.72 (95% CI: 0.59-0.85)

AUC: 0.94 (95% CI: 0.91-0.98)

(A) The ability of I-CARS to effectively stratify patients on the basis of their probability of cardiac response and cardiac recovery was validated in the Utah Cardiac

Recovery program cohort. The area under the ROC curve (AUC) demonstrated (B) fair discrimination by I-CARS for cardiac response and excellent discrimination for

cardiac recovery (C). CI ¼ confidence interval; other abbreviations as in Figure 3.

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(cut-points selected based on our previous research)(25), herein termed “cardiac responders” (n ¼ 27); andsecond, patients within this group who had theirLVAD explanted due to “cardiac recovery” (n ¼ 11).The evaluation protocol for LVAD explantation usedis described in the Online Appendix.

I-CARS was used to stratify patients in the valida-tion cohort on the basis of their probability of cardiacresponse and cardiac recovery. Patients in thehigh probability category experienced significantimprovement in myocardial function, with 50%experiencing cardiac response and 39% experiencingcardiac recovery (Figure 4A). I-CARS demonstrated agood performance in discriminating cardiac response(AUC: 0.72; 95% CI: 0.59 to 0.85) (Figure 4B) andcardiac recovery (AUC: 0.94; 95% CI: 0.91 to 0.98)(Figure 4C) in the UCAR validation cohort.

In addition, I-CARS was able to stratify patients inthe INTERMACS cohort (7,084 patients with echo-cardiographic follow-up) on the basis of their proba-bility of cardiac response, which occurred in 10%,13%, and 29% of patients in the low, intermediate,and high probability groups, respectively, albeit witha lower discrimination power (AUC: 0.58; 95% CI: 0.56to 0.60).

In the INTERMACS cohort, 1-year follow-up post-LVAD explantation was available in 21 patients. Ofthese patients, 18 were alive, 1 died, and 2 underwenttransplantation. In the UCAR program, after a medianfollow-up of 271 days (interquartile range: 182 to 442days) after LVAD explantation (n ¼ 11), 3 patients hadrecurrent HF (1 patient died, 1 patient underwenttransplantation, and the other patient remains stableon HF medical therapy).

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DISCUSSION

The maladaptive response to volume and pressureoverload leading to myocardial remodeling haslong been implicated in the progressive myocardialdysfunction observed in HF (33,34). Left ventricularunloading by mechanical support has the potential todisrupt the vicious cycle of volume and pressureoverload leading to cardiac remodeling. Severalstudies have shown reverse remodeling in LVAD-supported patients, in some sufficient to allow forexplantation of the device (17,18,22,35–40). Theseobservations have opened the gateway to the field ofLVAD-induced cardiac recovery. However, the inci-dence of cardiac recovery observed in these studieshas varied widely, thus promoting confusion anddisbelief that threatens the progress of this field.

INTERMACS, which has captured data on >15,000US Food and Drug Administration–approved LVADimplants in the United States, provides a robust op-portunity to examine cardiac recovery and LVADexplantation. In this contemporary analysis, weconfirmed, in general terms, that cardiac recoveryleading to pump removal is an infrequently reportedevent. Our study’s main finding, however, is thatonce a patient is identified as a potential candidatefor cardiac recovery by an LVAD team (i.e., a prioridesignation of BTR), the incidence of cardiac recoveryincreases 9-fold. This finding begs the question: whyis the incidence of cardiac recovery higher in the BTRstrategy patients compared with patients bridged totransplant or destination therapy?

The identification of patient characteristics associ-atedwith a higher probability of cardiac recovery couldpartially explain differences in recovery ratesobserved between patients bridged with an a prioriBTR strategy versus a non-BTR strategy. Patientcharacteristics and the study population’s diversity inits propensity for cardiac recovery have shown a sig-nificant impact on the rates of cardiac recovery inprevious BTR studies (28). INTERMACS patientsimplanted with an a priori BTR strategy were younger,and more frequently had nonischemic cardiomyopa-thy and shorter duration of HF; these characteristicshave previously been linked to a higher probability ofcardiac recovery (23,25). Additional factors, includingpost-LVAD management, likely contributed to theobserved differences in cardiac recovery between BTRand non-BTR patients. This is suggested by the factthat the incidence of cardiac recovery in BTR patientswas higher than in non-BTR patients, even when pa-tients have a similar cardiac recovery profile: 25%versus 8% for I-CARS $7 and 5% versus 1% for I-CARSbetween 4 and 6 (Central Illustration).

In terms of post-implant management, most LVADcenters do not have established clinical or researchBTR programs, nor do they have protocols to seriallymonitor the structural and functional myocardialchanges in these patients that ultimately could leadto cardiac recovery. As a result, unless a patient isconsidered to have the potential for cardiac recovery(an a priori BTR strategy), the occurrence of cardiacrecovery will be underappreciated (24). It is alsopossible that uncertainty regarding outcomes afterLVAD explantation and inexperience of LVAD teamsin managing these patients could affect the decisionto proceed with device removal. For instance, deviceexplantation due to cardiac recovery occurred in1.3% of patients in the INTERMACS cohort, whereas afavorable “cardiac response” occurred in an addi-tional 12.6% of patients who ultimately did not havetheir device explanted. Considering that 97% of the“cardiac responders” were not explanted and wereimplanted by using a non-BTR strategy, a change instrategy would potentially raise the incidence ofcardiac recovery to approximately 14%.

Similarly, most of these patients are not subjectedto rigorous LVAD weaning protocols, with predefinedLVAD explantation criteria and protocols for adjuvantdrug therapy that have been shown to be helpful inpromoting cardiac recovery, although such protocolsare unlikely unless an interest in cardiac recoveryexists (17–19,36,41). However, a comprehensive eval-uation of such recovery protocols to support this hy-pothesis was not possible from this registry.

Regarding pharmacotherapy in the INTERMACScohort, there were no differences in the use of anti-remodeling agents after LVAD implantation betweenBTR and non-BTR strategy patients (data not shown).However, patients experiencing cardiac recoverywere more often undergoing adjuvant drug therapycompared with patients who did not recover (OnlineTable 5). The probability of cardiac recovery was55% higher with the use of mineralocorticoid receptorantagonists and approximately 250% higher with theuse of beta-blockers and ACE inhibitors or ARBs.

Interestingly, patients who experienced cardiacrecovery were less frequently receiving beta-blockersand other neurohormonal inhibitors at the time ofLVAD placement, compared with patients withoutrecovery. This finding was shown to be a predictor ofreverse remodeling and cardiac recovery (42).

Although the identification of several characteris-tics likely to enhance the probability of cardiacrecovery in a given patient may have contributed tothe higher incidence of recovery in the BTR patients,better characterization of these patients is needed tomore effectively target efforts and maximize results.

CENTRAL ILLUSTRATION LVAD-Induced Cardiac Recovery

Wever-Pinzon, O. et al. J Am Coll Cardiol. 2016;68(14):1540–53.

This study evaluated true incidence of cardiac recovery in patients from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) who

received a left ventricular assist device (LVAD), some as an a priori bridge-to-recovery (BTR) strategy. A predictive model of cardiac recovery led to the creation of an

INTERMACS Cardiac Recovery Score (I-CARS) denoting tiered probability of recovery, which was validated through a Utah Cardiac Recovery (UCAR) program cohort.

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For instance, BTR patients who failed to recovertended to be older, had a longer duration of HF his-tory (40% with a duration >2 years), and more oftenhad previous cardiac surgeries (Online Table 2).

To further refine the “phenotype” of the idealcandidate for cardiac recovery, we developed a sim-ple clinical predictive model (i.e., the I-CARS) thateffectively stratified patients in the derivation cohorton the basis of probability of cardiac recovery. Moreimportantly, in those patients implanted with a BTRstrategy, a high probability score suggested a 24%probability of cardiac recovery. We validated I-CARS

in an independent cohort, showing good discrimina-tion and a 39% recovery rate in patients with a highprobability score. (The Online Appendix presents anI-CARS calculator.) Sustainability of cardiac recoveryafter LVAD explantation is obviously a major concern.The Berlin group experience showed a 3-year freedomfrom HF recurrence of 69% after LVAD explantation(43). Similarly encouraging outcomes have alsobeen reported by the Harefield program, inwhich post-explantation survival was similar to post-transplantation survival (44). Outcomes data afterLVAD explantation in the INTERMACS are limited

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: Suf-

ficient recovery of cardiac function to allow device

removal occurs in only a small fraction of patients

with LVADs. However, the odds improve substantially

for those <50 years of age with a diagnosis of noni-

schemic cardiomyopathy within 2 years and preserved

renal function in whom an automatic defibrillator

has not been implanted and the left ventricle has not

dilated beyond 6.5 cm.

TRANSLATIONAL OUTLOOK: Studies evaluating

biomarkers and molecular and metabolic predictors of

cardiac recovery in conjunction with clinical predictors

should be undertaken.

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(11% of explanted patients) and, as such, should beviewed with caution. The preliminary experience inour program after device removal was favorable;nevertheless, results from larger scale, prospectivestudies addressing this question are needed.

STUDY LIMITATIONS. This study was based on aretrospective analysis of a national registry with theknown limitations of this type of study design,including lack of data on patient selection, moni-toring and weaning protocols, and explantationcriteria. Importantly, data on outcomes after LVADexplantation are limited. In addition, some patientswere excluded from the multivariable analysis andpredictive model due to missing data, which couldhave introduced a selection bias. We also dichoto-mized variables, a strategy that simplifies creation ofa risk score but has the potential of providing lessrefined information.

CONCLUSIONS

LVAD-induced cardiac recovery is a real and under-recognized phenomenon. Its incidence was higher inpatients for whom their LVAD was implanted with ana priori intent of cardiac recovery. I-CARS, a simplepredictive score system created by using 6 clinicalfactors, predicted individual probabilities of cardiacrecovery and may help in directing patient selectionand adjuvant therapy approaches. Further valida-tion of this bridge-to-pump removal strategy has

significant patient and fiscal impacts by potentiallyreducing resource utilization and morbidity associ-ated with long-term mechanical support and trans-plantation in patients likely to achieve cardiacrecovery.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Craig H. Selzman, Division of Cardiothoracic Surgery,University of Utah Health Sciences Center, 30 North1900 East, SOM 3C 127, Salt Lake City, Utah 84132.E-mail: craig.selzman@hsc.utah.edu.

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KEY WORDS bridge, explantation, heartfailure, unloading

APPENDIX For an expanded Methods sectionas well as tables and figures, and I-CARScalculator, please see the online version ofthis article.