Global and Disease-Specific Health Status in Patients Undergoing

Continuous-Flow Left Ventricular Assist Device Placement

Kelsey Flint, MD University of Colorado School of Medicine

Division of Cardiology General Cardiology Fellow

Survival after LVAD

Survival curve for all continuous-flow LVADs in a clinical database

Kirklin JHLT 2014

Risk Models for Survival After LVAD RV Failure Score MELD MELD

excluding INRDTRS HMRS

Bilirubin X X X

INR X X X

Creatinine/BUN X X X X X

Vasopressor use X X

AST X X

Age X

Albumin X X

Center volume ≤ 15 X

Pulmonary artery pressure X X

Platelet count X

Hematocrit X

AUC derivation 0.73 -- -- 0.89 0.77

AUC validation 0.61-0.66 0.66 -- 0.60 0.64

Reproduced from Levy JACC 2013

Health Status and Heart Failure

Heart failure-specific health status is associated with death and hospitalization in patients with heart failure who were medically treated in the outpatient setting.

Heidenreich JACC 2006

Health Status and CABG

The physical component score of the SF-36 had greater impact on 6-month mortality than creatinine or smoking history

• Health status is also associated with mortality following cardiac surgery, such as CABG

Rumsfeld JAMA 1999

Health Status and Outcomes After LVAD

Health Status and Outcomes After LVAD

Flint JHLT 2013

Health Status and Outcomes After LVAD

• Therefore we decided to further study health status in the LVAD setting:– Outside the clinical trial setting, as patients

entered in to the clinical trials had uniformly very poor health status

– With a generic as well as heart failure-specific health status measure

– Measured before and shortly (3 months) after LVAD placement

Methods • The INTERMACS (Interagency Registry for

Mechanically Assisted Circulatory Support) database is a prospective, observational registry of all FDA-approved LVADs placed at participating centers (N-158)– Health status data are collected pre-operatively and

after LVAD at 3 ,6 and 12 months, then yearly – Hospitalization and mortality outcomes are recorded

as they occur and at each follow-up period– The INTERMACS protocol was approved by each

institution’s IRB, and individual patient consent was obtained when mandated by the local IRB

Methods – Statistics • Heart failure-specific health status – KCCQ • Global health status – Euroqol 5D visual analog scale (VAS)• Based on the skewed distribution of health status scores

towards poor health status, KCCQ and VAS scores were broken down into quartiles

• Inverse propensity weighting (IPW) was used to minimize bias associated with missing health status scores (40%)

• Kaplan-Meier method assessed the association between health status and mortality and hospitalization

• Incremental prognostic value of health status was assessed using IPW-weighted Cox proportional hazards– We used the variables included in the HeartMate II Risk Model

(age, albumin, creatinine, INR, center volume) as the base model

Table 1Overall

N=3836

KCCQ Q1

N= 552

KCCQ Q2

N= 558

KCCQ Q3

N=556

KCCQ Q4

N=559

P-value

Age 0.29219-20 150 (3.9) 12 (2.2) 13 (2.3) 16 (2.9) 20 (3.6)30-39 242 (6.3) 34 (6.2) 36 (6.5) 36 (6.5) 28 (5)40-49 513 (13.4) 90 (16.3) 70 (12.5) 65 (11.7) 68 (12.2)50-59 972 (25.3) 141 (25.5) 131 (23.5) 145 (26.1) 126 (22.5)60-69 1330 (34.7) 189 (34.2) 207 (37.1) 177 (31.8) 212 (37.9)70-79 597 (15.6) 80 (14.5) 97 (17.4) 111 (20) 101 (18.1)≥ 80 32 (0.8) 6 (1.1) 4 (0.7) 6 (1.1) 4 (0.7)

Female 807 (21) 26.8% 23.8% 17.4% 14.7% <0.001

Overall

N=3836

KCCQ Q1

N= 552

KCCQ Q2

N= 558

KCCQ Q3

N=556

KCCQ Q4

N=559

P-value

INTERMACS profile <0.0011 (Critical cardiogenic shock) 500 (13) 66 (12) 27 (4.8) 23 (4.1) 26 (4.7)

2 (Progressive decline) 1361 (35.5) 237 (42.9) 197 (34.2) 188 (33.8) 195 (34.9)3 (Stable but inotrope dependent) 1193 (31.1) 162 (29.3) 201 (36) 202 (36.3) 213 (38.1)

4 (Resting symptoms) 608 (15.8) 73 (12.2) 117 (21) 110 (19.8) 101 (18.1)5 (Exertion intolerant) 112 (2.9) 7 (1.2) 14 (2.5) 25 (4.5) 13 (2.3)

6 (Exertion limited) 33 (0.9) 2 (0.4) 3 (0.5) 5 (0.9) 5 (0.9)7 (Advanced NYHA III) 29 (0.8) 5 (0.9) 5 (0.9) 3 (0.5) 6 (1.1)

Table 1, continued Overall

N=3836

KCCQ Q1

N= 552

KCCQ Q2

N= 558

KCCQ Q3

N=556

KCCQ Q4

N=559

P-value

Device strategy 0.110

Bridge to transplant

788 (20.5) 97 (17.6) 112 (20.1) 102 (18.3) 141 (25.2)

Bridge to decision 1,329 (34.6) 169 (30.6) 178 (32) 183 (32.9) 167 (29.9)

Destination therapy

1,694 (44.2%) 282 (51.1) 266 (47.7) 269 (48.4) 248 (44.4)

Other 25 (0.7) 4 (0.7) 2 (0.4) 2 (0.4) 3 (0.6)

Dialysis within 48 hrs

40 (1) 9 (1.6) 1 (0.2) 1 (0.2) 2 (0.4) 0.005

Mechanical ventilation

210 (5.5) 20 (3.6) 10 (1.8) 10 (1.8) 12 (2.1) 0.127

IABP 918 (23.9) 146 (26.4) 89 (15.9) 86 (15.5) 71 (12.7) <0.001

Inotropes 3097 (80.7) 461 (83.5%) 449 (80.5) 429 (77) 446 (79.8) 0.116

Creatinine (mg/dl) 1.4 ± 0.6 1.4 ± 0.6 1.4 ± 0.8 1.4 ± 0.6 1.4 ± 0.6 0.880

Hemoglobin (g/dl) 11.4 ± 2.1 11.2 ± 2.1 11.6 ± 2.0 11.8 ± 2.0 11.8 ±2.1 <0.001

Sodium (mmol/L) 135.0 ± 4.7 134.1 ± 4.9 134.9 ± 4.8 135.3 ± 4.3 135.5 ± 4.1 <0.001

Albumin (g/dl) 3.4 ± 0.7 3.4 ± 0.6 3.5 ± 0.7 3.5 ± 0.6 3.6 ± 0.6 <0.001

INR 1.3 ± 0.4 1.3 ± 0.5 1.3 ± 0.4 1.3 ± 0.5 1.3 ± 0.3 0.165

Baseline and 3-month Health Status and Survival

Only 3-month KCCQ was associated with 2-year mortality

Baseline and 3-month Health Status and Rehospitalization

3-month KCCQ and VAS score quartiles were associated with 24-month rehospitalizaiton rate

Incremental Prognostic Value of Baseline and 3-month Health Status

C-statistic (base clinical score only)

C-statistic (base clinical + health status measure)

C-statistic (base clinical score only)

C-statistic (base clinical + health status measure)

Outcome: 24-month mortality

Outcome: 24-month rehospitalization

Baseline KCCQ (N=2225) 0.60 0.61 0.51 0.50

Baseline EQ-5D VAS (N=2205)

0.60 0.60 0.51 0.52

3-month KCCQ(N=2060) 0.60 0.66 0.52 0.55

3-month EQ-5D VAS (N=2005)

0.59 0.60 0.52 0.54

Base clinical score was comprised of the variables included in the HeartMate II Risk Score (Cowger JACC 2013) – age, albumin, creatinine, center volume, INR

Limitations

• Nearly 40% of patients were missing health status data, introducing significant selection bias– We attempted to account for this bias using IPW

• We were not able to characterize causes of death and hospitalization. This information would be useful as device-related complications leading to death or rehospitalization would not be expected to correlate with patient-reported outcomes.

Clinical Implications

• Very poor pre-operative health status should not preclude LVAD implantation

• 3-month KCCQ score was associated with long-term mortality, therefore serial assessments of heart failure-specific health status may help inform prognosis and goals of care discussions

Implications for Future Study• 24-month rehospitalization is poorly predicted by

the HeartMate II Risk Score or health status– Further study is needed to better characterize, and

eventually predict rehospitalization in this population beyond the existing single-center descriptions

• 24-month mortality is moderately-well predicted

by the HeartMate II Risk Score and health status – Further study is needed to further characterize

patient, device and institution-related factors associated with mortality

Summary

• Pre-operative heart failure-specific and global health status are not predictive of mortality or rehospitalization after LVAD – Poor health status does not necessarily preclude

LVAD

• 3-month KCCQ adds incremental prognostic value to an established risk model for predicting 24-month mortality after LVAD – Serial health status measurements after LVAD may be

clinically useful

Thank you!

• INTERMACS DAAP • Kathy Grady• MAHI for analytic support and guidance – John Spertus, MD– Fengming Tang, MS

• Mentors and colleagues– Larry Allen, MD, MHS – Timothy Fendler, MD

Questions?

Reference slides

Reference material

Survival after DT HMII during the the clinical trial vs. post-approval

Reference material • Retrospective study examining the predictive value of the HMII Risk Score in all patients implanted with a CF-LVAD at Columbia University Medical Center from 3/2004 to 9/2012 (N=201).

• The HMII RS had a c-stat of 0.56 for the outcome of 90-day mortality in the Columbia population

Thomas JHLT 2014

Reference

• The HMII RS was validated at Barnes-Jewish Hospital in 269 consecutive patients receiving the HMII (June 2005 – June 2013).

• The HMII RS had a c-stat of 0.70 for 90-day mortality

Adamo JACC HF 2015

ReferenceArticle Population Health Status

MeasureResult

Soto Circ 2004 1516 patients in the EPHESUS trial

KCCQ KCCQ 1 month after MI complicated by HF was associated with 1-year mortality and hospitalization

Kosiborod Circ 2007

1358 patients in the EPHESUS trial

KCCQ Change in KCCQ from 1 to 3 months after MI complicated by HF was associated with long-term all-cause mortality and rehospitalization

Kato Circ J 2011

114 outpatients with HF

MLWHF Worse health status was associated with increased risk of cardiac death or hospitalization for HF and all-cause mortality

Konstam Am J Card 1996

6797 patients in the SOLVD trial

HRQOL measure created from established sources

HRQOL was associated with subsequent mortality and HF hospitalizations

Additional studies examining the prognostic value of health status in medically treated patients with heart failure.

ReferenceArticle Population Health Status

MeasureResult

Curtis Medical Care 2002

1,778 patients undergoing CABG under usual care

SF-36 Worse PCS score was associated with increased in-hospital mortality and prolonged length of stay

Lindsay Heart 2001

183 patients undergoing CABG

SF-36 Worse pre-operative health status was associated with angina 10 months post-CABG

Koch Circ 2007 6,305 patients who underwent CABG

Duke Activity Status Index

Worse pre-operative and 6 or 12 month post-operative DASI were associated with long-term mortality

Additional studies examining the prognostic value of health status in patients undergoing CABG.

Continuous-Flow LVAD

• There are continuous-flow LVAD’s approved by the FDA – the HeartMate II and the Heartware

• Blood is propelled from the LV to the aorta by a pump with a rotor that rotates in response to the electromotive forces of the motor.

• HeartMate II is an axial-flow pump – cylindrical rotor with helical blades, causing blood to accelerate in the direction of the rotor’s axis

• Heartware is a centrifugal-flow pump – rotors are shaped to accelerate blood circumferentially (towards the outer rim of the pump). Unlike the HeartMate II, the Heartware has no mechanical bearings or points of contact between the impeller and the pump housing

Quantifying and Qualifying Morbidity in LVAD Candidates

Heart failure-specific health status, as measured by the KCCQ, may help capture LVAD-responsive frailty, which likely does not influence outcomes post-LVAD because LVAD-responsive components of a patient’s condition should be largely reversed.

Flint Circ HF 2012

Methods – Health Status Measures • Kansas City Cardiomyopathy Questionnaire (KCCQ)

– Measures heart failure-specific health status in 5 domains: physical limitation, heart failure symptoms, social limitation, self-efficacy, health-related quality of life

– Answers to questions are converted into a scale of 0-100, with higher scores indicating worse health status

• Euroqol 5-Dimensions (EQ-5D) – Measures global health status with the EQ-5D index and the visual

analog scale (VAS) – The EQ-5D index is weighted to societal-based utilities to calculate

quality adjusted life years – The VAS asks patients to indicate on a 100mm line how they would

rate their overall health from 0-100, with 0 being the worst health imaginable

Patients in the INTERMACS Registry

N=11,162

Enrolled prior to mandatory health status reporting

N=5,854

Did not receive continuous-flow

LVADN=1,472

Continuous-flow LVAD N=9,690

Eligible for analysis: N=3,836

Baseline KCCQN=2,225

Baseline VASN=2,205

3-month KCCQN=2,060

3-month VASN=2,005

Missing: N=1,61129% too sick, 29% enrolled too late

N=1,63133% too sick, 33% enrolled too late

N=1,77663% coordinator too

busy, 32% unspecified

N=1,83148% coordinator too

busy; 21% unspecified

Methods: Final patient

cohort selection

Results Quartile 1 Quartile 2 Quartile 3 Quartile 4 Total

KCCQ score, pre-operative

14.3 (9.6, 18.2) 28.1 (25.3, 31.5) 41.1 (37.5, 45.6) 63.8 (56.3, 74.5) 34.6 (21.4, 50.5)

VAS score, pre-operative

10.0 (5.0, 20.0) 30.5 (30.0, 40.0) 50.0 (50.0, 60.0) 75.0 (70.0, 84.0) 43.0 (25.0, 65.0)

KCCQ score, 3-month

43.4 (34.8, 49.0) 62.2 (58.3, 65.6) 76.0 (72.9, 79.2) 89.6 (85.7, 93.8) 69.3 (54.2, 82.3)

VAS score, 3 month

40.0 (9.0, 50.0) 70.0 (62.0, 70.0) 80.0 (75.0, 80.0) 90.0 (88.0, 95.0) 75.0 (60.0, 85.0)

Median (IQR) of the health status scores in each quartile range

Results

Discussion• Pre-operative heart failure-specific and global health status

were not associated with 24- month mortality or rehospitalization following LVAD placement

• 3-month KCCQ score was associated with 24-month mortality, and added incremental prognostic value when added to a previously validated base clinical model (Heartmate II Risk Model)

• 3-month KCCQ and VAS scores were associated with 24-month rehospitalization but did not add prognostic value to the Heartmate II Risk Model

• In general, the predictive value of the Heartmate II Risk Model and health status were moderate for the outcome of mortality, and poor for the outcome of hospitalization

Discussion

• LVAD is a significant intervention aimed at reversing the hemodynamic effects of advanced heart failure– Unlike medical management of heart failure or

CABG, LVAD may potentially reverse the adverse effects of heart failure

– Therefore, pre-operative health status may no longer be relevant

Discussion• Heart failure-specific health status may reflect LVAD-responsive frailty.

• Therefore low heart failure-specific health status by 3 months after LVAD (when most patients will have recovered from surgery) portends a poor prognosis by signifying lack of the expected benefit from the device.

Flint Circ HF 2012